Substituted furo[2,3-b]pyridine derivatives

ABSTRACT

Novel compounds of the structural formula (I) are antagonists and/or inverse agonists of the Cannabinoid-1 (CB1) receptor and are useful in the treatment, prevention and suppression of diseases mediated by the CB1 receptor. The compounds of the present invention are useful as centrally acting drugs in the treatment of psychosis, memory deficits, cognitive disorders, migraine, neuropathy, neuro-inflammatory disorders including multiple sclerosis and Guillain-Barre syndrome and the inflammatory sequelae of viral encephalitis, cerebral vascular accidents, and head trauma, anxiety disorders, stress, epilepsy, Parkinson&#39;s disease, movement disorders, and schizophrenia. The compounds are also useful for the treatment of substance abuse disorders, the treatment of obesity or eating disorders, as well as the treatment of asthma, constipation, chronic intestinal pseudo-obstruction, and cirrhosis of the liver.

CROSS-REFERENCE TO RELATED APPLICATIONS

Not applicable.

BACKGROUND OF THE INVENTION

Marijuana (Cannabis sativa L.) and its derivatives have been used forcenturies for medicinal and recreational purposes. A major activeingredient in marijuana and hashish has been determined to beΔ⁹-tetrahydrocannabinol (Δ⁹-THC). Detailed research has revealed thatthe biological action of Δ⁹-THC and other members of the cannabinoidfamily occurs through two G-protein coupled receptors termed CB1 andCB2. The CB1 receptor is primarily found in the central and peripheralnervous systems and to a lesser extent in several peripheral organs. TheCB2 receptor is found primarily in lymphoid tissues and cells. Threeendogenous ligands for the cannabinoid receptors derived fromarachidonic acid have been identified (anandamide, 2-arachidonoylglycerol, and 2-arachidonyl glycerol ether). Each is an agonist withactivities similar to Δ⁹-THC, including sedation, hypothermia,intestinal immobility, antinociception, analgesia, catalepsy,anti-emesis, and appetite stimulation.

The genes for the respective cannabinoid receptors have each beendisrupted in mice. The CB1^(−/−) receptor knockout mice appeared normaland fertile. They were resistant to the effects of Δ⁹-THC anddemonstrated a strong reduction in the reinforcing properties ofmorphine and the severity of withdrawal syndrome. They also demonstratedreduced motor activity and hypoalgesia. The CB2^(−/−) receptor knockoutmice were also healthy and fertile. They were not resistant to thecentral nervous system mediated effects of administered Δ⁹-THC. Therewere some effects on immune cell activation, reinforcing the role forthe CB2 receptor in immune system functions.

Excessive exposure to Δ⁹-THC can lead to overeating, psychosis,hypothermia, memory loss, and sedation. Specific synthetic ligands forthe cannabinoid receptors have been developed and have aided in thecharacterization of the cannabinoid receptors: CP55,940 (J. Pharmacol.Exp. Ther. 1988, 247, 1046-1051); WIN55212-2 (J. Pharmacol. Exp. Ther.1993, 264, 1352-1363); SR¹⁴¹⁷¹⁶A (FEBS Lett. 1994, 350, 240-244; LifeSci. 1995, 56, 1941-1947); and SR144528 (J. Pharmacol. Exp. Ther. 1999,288, 582-589). The pharmacology and therapeutic potential forcannabinoid receptor ligands has been reviewed (Exp. Opin. Ther. Patents1998, 8, 301-313; Ann. Rep. Med. Chem., A. Doherty, Ed.; Academic Press,NY 1999, Vol. 34, 199-208; Exp. Opin. Ther. Patents 2000, 10, 1529-1538;Trends in Pharma. Sci. 2000, 21, 218-224). There is at least one CB1modulator characterized as an inverse agonist or an antagonist,N-(1-piperidinyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide(SR141716A), in clinical trials for treatment of eating disorders atthis time. There still remains a need for potent low molecular weightCB1 modulators that have pharmacokinetic and pharmacodynamic propertiessuitable for use as human pharmaceuticals.

Treatment of asthma with CB1 receptor modulators (such as CB1 inverseagonists) is supported by the finding that presynaptic cannabinoid CB1receptors mediate the inhibition of noradrenaline release (in the guineapig lung)-(Europ. J. of Pharmacology, 2001, 431 (2), 237-244).

Treatment of cirrhosis of the liver with CB1 receptor modulators issupported by the finding that a CB1 receptor modulator will reverse thelow blood pressure observed in rats with carbon tetrachloride-inducedliver cirrhosis and will lower the elevated mesenteric blood flow andportal vein pressure (Nature Medicine, 2001, 7 (7), 827-832).

U.S. Pat. Nos. 5,624,941, 6,028,084, and 6,509,367, PCT PublicationsWO98/43636 and WO98/43635, and EP-658546 disclose substituted pyrazoleshaving activity against the cannabinoid receptors.

PCT Publications WO98/31227 and WO98/41519 also disclose substitutedpyrazoles having activity against the cannabinoid receptors.

PCT Publications WO98/37061, WO00/10967, and WO0/10968 disclose diarylether sulfonamides having activity against the cannabinoid receptors.

PCT Publications WO97/29079 and WO99/02499 disclose alkoxy-isoindolonesand alkoxy-quinolones as having activity against the cannabinoidreceptors.

U.S. Pat. No. 5,532,237 discloses N-benzoyl-indole derivatives havingactivity against the cannabinoid receptors.

U.S. Pat. Nos. 4,973,587, 5,013,837, 5,081,122, 5,112,820, and 5,292,736disclose aminoalkylindole derivatives as having activity against thecannabinoid receptors.

PCT publication WO 01/58869 discloses pyrazoles, pyrroles and imidazolecannabinoid receptor modulators useful for treating respiratory andnon-respiratory leukocyte activation-associated disorders.

U.S. Pat. No. 6,355,631, U.S. Pat. No. 6,479,479 and PCT publications WO01/64632, 01/64633, and 01/64634 assigned to Aventis are directed toazetidine derivatives as cannabinoid antagonists.

Other cannabinoid receptor modulating compounds are disclosed in WO01/70700, WO 02/076949; WO 03/026647; WO 03/026648; WO 03/027069; WO03/027076; and WO 03/027114.

The compounds of the present invention are modulators of theCannabinoid-1 (CB1) receptor and are useful in the treatment, preventionand suppression of diseases mediated by the Cannabinoid-1 (CB1)receptor. In particular, compounds of the present invention areantagonists or inverse agonists of the CB1 receptor. The invention isconcerned with the use of these compounds to modulate the Cannabinoid-1(CB1) receptor. As such, compounds of the present invention are usefulas centrally acting drugs in the treatment of psychosis, memorydeficits, cognitive disorders, migraine, neuropathy, neuro-inflammatorydisorders including multiple sclerosis and Guillain-Barre syndrome andthe inflammatory sequelae of viral encephalitis, cerebral vascularaccidents, and head trauma, anxiety disorders, stress, epilepsy,Parkinson's disease, movement disorders, and schizophrenia. Thecompounds are also useful for the treatment of substance abusedisorders, particularly to opiates, alcohol, marijuana, and nicotine.The compounds are also useful for the treatment of eating disorders byinhibiting excessive food intake and the resulting obesity andcomplications associated therewith, including left ventricularhypertrophy. The compounds are also useful for the treatment ofconstipation and chronic intestinal pseudo-obstruction, as well as forthe treatment of asthma, and cirrhosis of the liver.

SUMMARY OF THE INVENTION

The present invention is concerned with novel substituted furo[2,3-b]pyridine derivatives of general Formula I:

and pharmaceutically acceptable salts thereof which are antagonistsand/or inverse agonists of the Cannabinoid-1 (CB1) receptor and areuseful in the treatment, prevention or suppression of diseases mediatedby the Cannabinoid-1 (CB1) receptor. The invention is concerned with theuse of these novel compounds to selectively antagonize the Cannabinoid-1(CB1) receptor. As such, compounds of the present invention are usefulas centrally acting drugs in the treatment of psychosis, memorydeficits, cognitive disorders, migraine, neuropathy, neuro-inflammatorydisorders including multiple sclerosis and Guillain-Barre syndrome andthe inflammatory sequelae of viral encephalitis, cerebral vascularaccidents, and head trauma, anxiety disorders, stress, epilepsy,Parkinson's disease, movement disorders, and schizophrenia. Thecompounds are also useful for the treatment of substance abusedisorders, particularly to opiates, alcohol, marijuana, and nicotine,including smoking cessation. The compounds are also useful for thetreatment of obesity or eating disorders associated with excessive foodintake and complications associated therewith, including leftventricular hypertrophy. The compounds are also useful for the treatmentof constipation and chronic intestinal pseudo-obstruction. The compoundsare also useful for the treatment of cirrhosis of the liver. Thecompounds are also useful for the treatment of asthma.

The present invention is also concerned with treatment of theseconditions, and the use of compounds of the present invention formanufacture of a medicament useful in treating these conditions. Thepresent invention is also concerned with treatment of these conditionsthrough a combination of compounds of formula I and other currentlyavailable pharmaceuticals.

The invention is also concerned with pharmaceutical formulationscomprising one of the compounds as an active ingredient.

The invention is further concerned with processes for preparing thecompounds of this invention.

DETAILED DESCRIPTION OF THE INVENTION

The compounds used in the methods of the present invention arerepresented by structural formula I:

wherein;

-   R¹ is selected from:    -   (1) C₁₋₁₀alkyl,    -   (2) C₂₋₁₀ alkenyl,    -   (3) C₂₋₁₀alkynyl,    -   (4) —CN,    -   (5) —COR⁴,    -   (6) —S(O)_(m)R⁴,    -   (7) —S(O)₂NH(CO)_(n)NR^(e),    -   (8) cycloheteroalkyl,    -   (9) aryl, and    -   (10) heteroaryl,        wherein alkyl, alkenyl, and alkynyl are optionally substituted        with one, two, or three substituents independently selected from        R^(a), and cycloheteroalkyl, aryl and heteroaryl are optionally        substituted with one, two, or three substituents independently        selected from R^(b);-   R² is selected from:    -   (1) hydrogen,    -   (2) —NR⁵R⁶,    -   (3) —COR⁴,    -   (4) C₁₋₆alkyl,    -   (5) C₂₋₆ alkenyl,    -   (6) C₂₋₆alkynyl,    -   (7) aryl,    -   (8) arylC₁₋₆alkyl-,    -   (9) arylC₂₋₆alkenyl,    -   (10) heteroaryl,    -   (11) heteroarylC₁₋₆alkyl-i    -   (12) heteroarylC₂₋₆alkenyl,    -   (13) cycloheteroalkyl,    -   (14) hydroxyl, and    -   (15) OR^(g),        wherein alkyl, alkenyl, and alkynyl are optionally substituted        with one, two, or three substituents independently selected from        R^(a); and aryl, and heteroaryl, are optionally substituted with        one, two, or three substituents independently selected from        R^(b) and cycloheteroalkyl is optionally substituted with one,        two, three or four substituents independently selected from        R^(b) and oxo;-   R³ is selected from:    -   (1) hydrogen,    -   (2) C₁₋₆alkyl,    -   (3) C₁₋₆alkyloxy,    -   (4) trifluoromethyl,    -   (5) trifluoromethoxy,    -   (6) halo, and    -   (7) C₃₋₇cycloalkyl, wherein alkyl, and cycloalkyl are optionally        substituted with one, two, or three substituents independently        selected from R^(a);-   R⁴ is selected from:    -   (1) hydrogen,    -   (2) C₁₋₁₀alkyl,    -   (3) C₂₋₁₀alkenyl,    -   (4) C₂₋₁₀alkynyl,    -   (5) cycloalkyl,    -   (6) cycloalkyl-C₁₋₁₀alkyl,    -   (7) cycloheteroalkyl,    -   (8) cycloheteroalkyl-C₁₋₁₀ alkyl,    -   (9) aryl,    -   (10) heteroaryl,    -   (11) aryl-C₁₋₁₀alkyl,    -   (12) heteroaryl-C₁₋₁₀alkyl-,    -   (13) —OR^(e),    -   (14) —NR^(d)R^(e),    -   (15) —NH(CO)OR^(e), and    -   (16) —NR^(d)SO₂R^(e),        wherein alkyl, alkenyl, alkynyl and cycloalkyl are optionally        substituted with one, two, three or four substituents        independently selected from R^(a), and cycloheteroalkyl, aryl        and heteroaryl are optionally substituted with one, two, three        or four substituents independently selected from R^(b);-   R⁵ and R⁶ are each independently selected from:    -   (1) hydrogen,    -   (2) C₁₋₁₀alkyl,    -   (3) C₂₋₁₀ alkenyl,    -   (4) C₂₋₁₀alkynyl,    -   (5) aryl,    -   (6) cycloalkyl,    -   (7) heteroaryl    -   (8) trifluoromethyl,    -   (9) —C(O)—R^(c),    -   (10) —CO₂R^(c),    -   (11) —C(O)C(O)OR^(c),    -   (12) —C(O)C(O)NR^(e)R^(f),    -   (13) —S(O)_(m)R^(c), and    -   (14) —C(O)N(R^(d))S(O)_(m)R^(c),        wherein alkyl, alkenyl, alkynyl, and cycloalkyl may be        optionally substituted with one or two R^(a) substituents, and        aryl may be optionally substituted with one or two R^(b)        substituents,-   or R⁵ and R⁶ together form ═CH—N(R^(e))(R^(f));-   Ar¹ and Ar² are independently selected from:    -   (1) aryl,    -   (2) heteroaryl,        wherein aryl and heteroaryl are optionally substituted with one,        two, three or four substituents independently selected from        R^(b);-   each R^(a) is independently selected from:    -   (1) OR^(e),    -   (2) —NR^(d)S(O)_(m)R^(c),    -   (3) —NO₂,    -   (4) halogen,    -   (5) —S(O)_(m)R^(c),    -   (6) —SR^(e),    -   (7) —S(O)₂OR^(e),    -   (8) —S(O)_(m)NR^(e)R^(f),    -   (9) —NR^(e)R^(f),    -   (10) —O(CR^(e)R^(f))_(n)NR^(e)R^(f),    -   (11) —C(O)R^(c),    -   (12) —CO₂R^(c),    -   (13) —CO₂(CR^(e)R^(f))_(n)CONR^(e)R^(f),    -   (14) —OC(O)R^(c),    -   (15) —CN,    -   (16) —C(O)NR^(e)R^(f),    -   (17) —NR^(d)C(O)R^(c),    -   (18) —NR^(d)C(O)OR^(e),    -   (19) —NR^(d)C(O)NR^(d)R^(e),    -   (20) —CR^(d)(N—OR^(e)),    -   (21) CF₃,    -   (22) —OCF₃,    -   (23) C₃₋₈cycloalkyl, and    -   (24) cycloheteroalkyl;-   each R^(b) is independently selected from:    -   (1) R^(a),    -   (2) C₁₋₁₀alkyl,    -   (3) aryl,    -   (4) arylC₁₋₄alkyl,    -   (5) heteroaryl, and    -   (6) heteroarylC₁₋₄alkyl,        wherein aryl and heteroaryl are unsubstituted or substituted        with one, two or three substituents independently selected from        R^(h);-   each R^(C) is independently selected from:    -   (1) hydrogen,    -   (2) C₁₋₁₀alkyl,    -   (3) C₂₋₁₀ alkenyl,    -   (4) C₂₋₁₀alkynyl,    -   (5) C₁₋₈ perfluoroalkyl,    -   (6) cycloalkyl,    -   (7) cycloalkyl-C₁₋₁₀alkyl,    -   (8) cycloheteroalkyl,    -   (9) cycloheteroalkyl-C₁₋₁₀ alkyl,    -   (10) aryl,    -   (11) heteroaryl,    -   (12) aryl-C₁₋₁₀alkyl,    -   (13) heteroaryl-C₁₋₁₀alkyl, and    -   (14) —NR^(d)R^(d),        wherein alkyl, cycloalkyl, cycloheteroalkyl, phenyl, and        heteroaryl may be substituted with one or two R^(h)        substituents, and alkyl, cycloalkyl, cycloheteroalkyl may be        substituted on a carbon or sulfur atom with one or two oxo        substituents;-   each R^(d) is independently selected from hydrogen, C₁₋₁₀alkyl,    C₁₋₁₀alkylsulfonyl, arylsulfonyl and C₁₋₁₀alkylcarbonyl-, wherein    the alkyl may be unsubstituted or substituted with one, two or three    substituents independently selected from R^(h);-   R^(e) and R^(f) are independently selected from hydrogen,    C₁₋₁₀alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀alkynyl, trifluoromethyl,    cycloalkyl, cycloalkyl-C₁₋₁₀ alkyl, cycloheteroalkyl,    cycloheteroalkyl-C₁₋₁₀ alkyl, aryl, heteroaryl, aryl-C₁₋₁₀ alkyl,    and heteroaryl-C₁₋₁₀ alkyl at each occurrence; or-   when bonded to the same atom, R^(e) and R^(f) together with the atom    to which they are attached form a ring of 5 to 7 members containing    0, 1, or 2 heteroatoms independently selected from oxygen, sulfur    and nitrogen; and-   each R^(e) and R^(f) may be unsubstituted or substituted on a carbon    or nitrogen atom with one, two or three substituents selected from    R^(h);-   R^(g) is selected from:    -   (1) C₁₋₁₀alkyl,    -   (2) C₁₋₁₀alkylcarbonyl-,    -   (3) aryl,    -   (4) arylcarbonyl,    -   (5) C₁₋₁₀alkylsulfonyl, and    -   (6) arylsulfonyl,        wherein each alkyl may be unsubstituted or substituted with one,        two or three R^(a) substituents, and each aryl may be        unsubstituted or substituted with one, two or three R^(b)        substituents; each R^(h) is independently selected from:    -   (1) halogen,    -   (2) C₁₋₁₀alkyl,    -   (3) C₃₋₈cycloalkyl,    -   (4) cycloheteroalkyl,    -   (5) aryl,    -   (6) arylC₁₋₄alkyl,    -   (7) heteroaryl,    -   (8) heteroarylC₁₋₄alkyl,    -   (9) —OR^(e),    -   (10) —NR^(d)S(O)_(m)R^(e),    -   (11) —S(O)_(m)R^(c),    -   (12) —SR^(e),    -   (13) —S(O)₂OR^(e),    -   (14) —NR^(e)R^(e),    -   (15) —O(CR^(d)R^(d))_(n)NR^(e)R^(f),    -   (16) —C(O)R^(c),    -   (17) —CO₂R^(e),    -   (18) —CO₂(CR^(d)R^(d))_(n)CONR^(e)R^(f),    -   (19) —OC(O)R^(e),    -   (20) —CN,    -   (21) —C(O)NR^(e)R^(f),    -   (22) —NR^(d)C(O)R^(e),    -   (23) —OC(O)NR^(e)R^(f),    -   (24) —NR^(d)C(O)OR^(e),    -   (25) —NR^(d)C(O)NR^(e)R^(f),    -   (26) CF₃, and    -   (27) —OCF₃,-   m is selected from 1 and 2; and-   n is selected from 1, 2, and 3;    or a pharmaceutically acceptable salt thereof.

In one embodiment of the present invention, the compounds used in themethods of the present invention are represented by structural formulaI, wherein:

-   R¹ is selected from:    -   (1) C₁₋₁₀alkyl,    -   (2) C₂₋₁₀ alkenyl,    -   (3) C₂₋₁₀alkynyl    -   (4) —CN,    -   (5) —COR⁴,    -   (6) —S(O)_(m)R⁴,    -   (7) —S(O)₂NH(CO)_(n)NR^(e),    -   (8) aryl, and    -   (9) heteroaryl,        wherein alkyl, alkenyl, and alkynyl are optionally substituted        with one, with one, two, or three substituents independently        selected from R^(a), and aryl and heteroaryl are optionally        substituted with one, two, or three substituents independently        selected from R^(b);-   R² is selected from:    -   (1) hydrogen,    -   (2) —NR⁵R⁶,    -   (3) —COR⁴,    -   (4) C₁₋₆alkyl,    -   (5) C₂₋₆ alkenyl,    -   (6) C₂₋₆alkynyl,    -   (7) aryl,    -   (8) heteroaryl,    -   (9) cycloheteroalkyl,    -   (10) hydroxyl, and    -   (11) OR^(g),        wherein alkyl, alkenyl, and alkynyl are optionally substituted        with one, with one, two, or three substituents independently        selected from R^(a); and aryl, heteroaryl, and cycloheteroalkyl        are optionally substituted with one, two, or three substituents        independently selected from R^(b);-   R³ is selected from:    -   (1) hydrogen,    -   (2) C₁₋₆alkyl,    -   (3) C₁₋₆alkyloxy,    -   (4) trifluoromethyl,    -   (5) trifluoromethoxy,    -   (6) halo, and    -   (7) C₃₋₇cycloalkyl,    -   wherein alkyl, and cycloalkyl are optionally substituted with        one, two, or three substituents independently selected from        R^(a);-   R⁴ is selected from:    -   (1) hydrogen,    -   (2) C₁₋₁₀alkyl,    -   (3) C₂₋₁₀ alkenyl,    -   (4) C₂₋₁₀alkynyl,    -   (5) cycloalkyl,    -   (6) cycloalkyl-C₁₋₁₀alkyl;    -   (7) cycloheteroalkyl,    -   (8) cycloheteroalkyl-C₁₋₁₀ alkyl;    -   (9) aryl,    -   (10) heteroaryl,    -   (11) aryl-C₁₋₁₀alkyl, and    -   (12) heteroaryl-C₁₋₁₀alkyl-,    -   (13) —OR^(e),    -   (14) —NR^(d)R^(e),    -   (15) —NH(CO)R^(e),    -   (16) —NH(CO)OR^(e), and    -   (17) —NR^(d)SO₂R^(e),    -   wherein alkyl, alkenyl, alkynyl and cycloalkyl are optionally        substituted with one, two, three or four substituents        independently selected from R^(a), and cycloheteroalkyl, aryl        and heteroaryl are optionally substituted with one, two, three        or four substituents independently selected from R^(b);-   R⁵ and R⁶ are each independently selected from:    -   (1) hydrogen,    -   (2) C₁₋₁₀alkyl,    -   (3) C₂₋₁₀ alkenyl,    -   (4) C₂₋₁₀alkynyl,    -   (5) aryl,    -   (6) cycloalkyl,    -   (7) trifluoromethyl,    -   (8) —C(O)—R^(c),    -   (9) —CO₂R^(c), and-   —S(O)_(m)R^(C), wherein alkyl, alkenyl, alkynyl, and cycloalkyl may    be optionally substituted with one or two R^(a) substituents, and    aryl may be optionally substituted with one or two R^(b)    substituents;-   Ar¹ and Ar² are independently selected from:    -   (1) aryl,    -   (2) heteroaryl,    -   wherein aryl and heteroaryl are optionally substituted with one,        two, three or four substituents independently selected from        R^(b);-   each R^(a) is independently selected from:    -   (1) —OR^(e),    -   (2) —NR^(d)S(O)_(m)R^(c),    -   (3) —NO₂,    -   (4) halogen,    -   (5) —S(O)_(m)R^(c),    -   (6) —SR^(e),    -   (7) —S(O)₂OR^(e),    -   (8) —S(O)_(m)NR^(e)R^(f),    -   (9) —NR^(e)R^(f),    -   (10) —O(CR^(e)R^(f))_(n)NR^(e)R^(f),    -   (11) —C(O)R^(c),    -   (12) —CO₂R^(c),    -   (13) —CO₂(CR^(e)R^(f))_(n)CONR^(e)R^(f),    -   (14) —OC(O)R^(c),    -   (15) —CN,    -   (16) —C(O)NR^(e)R^(f),    -   (17) —NR^(d)C(O)R^(c),    -   (18) —NR^(d)C(O)OR^(e),    -   (19) —NR^(d)C(O)NR^(d)R^(e),    -   (20) —CR^(d)(N—OR^(e)),    -   (21) CF₃,    -   (22) —OCF₃,    -   (23) C₃₋₈cycloalkyl, and    -   (24) cycloheteroalkyl;-   each R^(b) is independently selected from:    -   (1) R^(a),    -   (2) C₁₋₁₀alkyl,    -   (3) aryl,    -   (4) arylC₁₋₄alkyl,    -   (5) heteroaryl, and    -   (6) heteroarylC₁₋₄alkyl;-   each R^(c) is independently selected from:    -   (1) hydrogen,    -   (2) C₁₋₁₀alkyl,    -   (3) C₂₋₁₀ alkenyl,    -   (4) C₂₋₁₀alkynyl,    -   (5) trifluoromethyl,    -   (6) cycloalkyl,    -   (7) cycloalkyl-C₁₋₁₀alkyl,    -   (8) cycloheteroalkyl,    -   (9) cycloheteroalkyl-C₁₋₁₀ alkyl,    -   (10) aryl,    -   (11) heteroaryl,    -   (12) aryl-C₁₋₁₀alkyl,    -   (13) heteroaryl-C₁₋₁₀alkyl, and    -   (14) —NR^(d)R^(d),        wherein alkyl, alkenyl, alkynyl, cycloalkyl, cycloheteroalkyl,        aryl, and heteroaryl may be substituted with one or two R^(h)        substituents;-   each R^(d) is independently selected from hydrogen and C₁₋₁₀alkyl;-   R^(e) and R^(f) are independently selected from hydrogen,    C₁₋₁₀alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀alkynyl, trifluoromethyl,    cycloalkyl, cycloalkyl-C₁₋₁₀ alkyl, cycloheteroalkyl,    cycloheteroalkyl-C₁₋₁₀ alkyl, aryl, heteroaryl, aryl-C₁₋₁₀ alkyl,    and heteroaryl-C₁₋₁₀ alkyl at each occurrence; or when bonded to the    same atom, R^(e) and R^(f) together with the atom to which they are    attached form a ring of 5 to 7 members containing 0, 1, or 2    heteroatoms independently selected from oxygen, sulfur and nitrogen;-   each R^(e) and R^(f) may be unsubstituted or substituted on a carbon    or nitrogen atom with one, two or three substituents selected from    R^(h);-   R^(g) is selected from:    -   (1) C₁₋₁₀alkyl,    -   (2) C₁₋₁₀alkylcarbonyl-,    -   (3) aryl,    -   (4) arylcarbonyl,    -   (5) C₁₋₁₀alkylsulfonyl, and    -   (6) arylsulfonyl,        wherein each alkyl may be unsubstituted or substituted with one,        two or three R^(a) substituents, and each aryl may be        unsubstituted or substituted with one, two or three R^(b)        substituents; each R^(h) is independently selected from:    -   (1) halogen,    -   (2) C₁₋₁₀alkyl,    -   (3) C₃₋₈cycloalkyl,    -   (4) cycloheteroalkyl,    -   (5) aryl,    -   (6) arylC₁₋₄alkyl,    -   (7) heteroaryl,    -   (8) heteroarylC₁₋₄alkyl,    -   (9) —OR^(e),    -   (10) —NR^(d)S(O)_(m)R^(e),    -   (11) —S(O)_(m)R^(c),    -   (12) —SR^(e),    -   (13) —S(O)₂OR^(e),    -   (14) —NR^(e)R^(e),    -   (15) —O(CR^(d)R^(d))_(n)NR^(e)R^(f),    -   (16) —C(O)R^(c),    -   (17) —CO₂R^(e),    -   (18) —CO₂(CR^(d)R^(d))_(n)CONR^(e)R^(f),    -   (19) —OC(O)R^(e),    -   (20) —CN,    -   (21) —C(O)NR^(e)R^(f),    -   (22) —NR^(d)C(O)R^(e),    -   (23) —OC(O)NR^(e)R^(f),    -   (24) —NR^(d)C(O)OR^(e),    -   (25) —NR^(d)C(O)NR^(e)R^(f),    -   (26) CF₃, and    -   (27) —OCF₃,-   m is selected from 1 and 2; and-   n is selected from 1, 2, and 3;    or a pharmaceutically acceptable salt thereof.

In one embodiment of the present invention, R¹ is selected from:

-   -   (1) C₁₋₁₀alkyl,    -   (2) C₂₋₁₀alkenyl,    -   (3) C₂₋₁₀alkynyl,    -   (4) —CN,    -   (5) —COR⁴,    -   (6) —S(O)_(m)R⁴,    -   (7) —S(O)₂NH(CO)_(n)NR^(e),    -   (8) cycloheteroalkyl,    -   (9) aryl, and    -   (10) heteroaryl,        wherein alkyl, alkenyl, and alkynyl are optionally substituted        with one, two, or three substituents independently selected from        R^(a), and cycloheteroalkyl, aryl and heteroaryl are are        optionally substituted with one, two, or three substituents        independently selected from R^(b).

In one class of this embodiment, R¹ is selected from:

-   -   (1) C₁₋₁₀alkyl,    -   (2) C₂₋₁₀ alkenyl,    -   (3) C₂₋₁₀alkynyl    -   (4) —CN,    -   (5) —COR⁴,    -   (6) S(O)_(m)R⁴,    -   (7) —S(O)₂NH(CO)_(n)NR^(e),    -   (8) aryl, and    -   (9) heteroaryl,        wherein alkyl, alkenyl, and alkynyl are optionally substituted        with one, with one, two, or three substituents independently        selected from R^(a), and aryl and heteroaryl are optionally        substituted with one, two, or three substituents independently        selected from R^(b);    -   In another class of this embodiment, R¹ is selected from:    -   (1) C₁₋₁₀alkyl,    -   (2) —CN,    -   (3) —COR⁴,    -   (4) —(O)₂R⁴,    -   (5) cycloheteroalkyl,    -   (6) aryl, and    -   (7) heteroaryl,        wherein alkyl is optionally substituted with one, two, or three        substituents independently selected from R^(a), and        cycloheteroalkyl, aryl and heteroaryl are optionally substituted        with one, two, or three substituents independently selected from        R^(b).

In another embodiment of the present invention, R¹ is selected from:

-   -   (1) C₁₋₆alkyl,    -   (2) C₂₋₆ alkenyl,    -   (3) C₂₋₆alkynyl    -   (4) cyano,    -   (5) C₁₋₆alkylcarbonyl,    -   (6) C₂₋₆ alkenylcarbonyl,    -   (7) C₂₋₆alkynylcarbonyl,    -   (8) cycloalkylcarbonyl,    -   (9) cycloalkyl-C₁₋₄alkylcarbonyl;    -   (10) cycloheteroalkylcarbonyl,    -   (11) cycloheteroalkyl-C₁₋₄ alkylcarbonyl;    -   (12) arylcarbonyl,    -   (13) heteroarylcarbonyl,    -   (14) aryl-C₁₋₄alkylcarbonyl,    -   (15) heteroaryl-C₁₋₄alkylcarbonyl-,    -   (16) C₁₋₆alkyloxycarbonyl,    -   (17) C₂₋₆ alkenyloxycarbonyl,    -   (18) C₂₋₆alkynyloxycarbonyl,    -   (19) trifluoromethyloxycarbonyl,    -   (20) cycloalkyloxycarbonyl,    -   (21) cycloalkyl-C₁₋₄alkyloxycarbonyl,    -   (22) cycloheteroalkyloxycarbonyl,    -   (23) cycloheteroalkyl-C₁₋₄ alkyloxycarbonyl,    -   (24) aryloxycarbonyl,    -   (25) heteroaryloxycarbonyl,    -   (26) aryl-C₁₋₄alkyloxycarbonyl,    -   (27) heteroaryl-C₁₋₄alkyloxycarbonyl,    -   (28) —CONR^(d)R^(e),    -   (29) —CONH(CO)OR^(e),    -   (30) —CONR^(d)SO₂R^(e),    -   (31) C₁₋₆alkylsulfonyl-,    -   (32) C₂₋₆ alkenylsulfonyl-,    -   (33) C₂₋₆alkynylsulfonyl-,    -   (34) cycloalkylsulfonyl-,    -   (35) cycloalkyl-C₁₋₄alkylsulfonyl-,    -   (36) cycloheteroalkylsulfonyl-,    -   (37) cycloheteroalkyl-C₁₋₄ alkylsulfonyl-,    -   (38) arylsulfonyl-,    -   (39) heteroarylsulfonyl-,    -   (40) aryl-C₁₋₄alkylsulfonyl-,    -   (41) heteroaryl-C₁₋₄alkylsulfonyl-,    -   (42) C₁₋₆alkyloxysulfonyl-,    -   (43) C₂₋₆ alkenyloxysulfonyl-,    -   (44) C₂₋₆alkynyloxysulfonyl-,    -   (45) trifluoromethyloxysulfonyl-,    -   (46) cycloalkyloxysulfonyl-,    -   (47) cycloalkyl-C₁₋₄alkyloxysulfonyl-,    -   (48) cycloheteroalkyloxysulfonyl-,    -   (49) cycloheteroalkyl-C₁₋₄ alkyloxysulfonyl-,    -   (50) aryloxysulfonyl-,    -   (51) heteroaryloxysulfonyl-,    -   (52) aryl-C₁₋₄alkyloxysulfonyl-,    -   (53) heteroaryl-C₁₋₄alkyloxysulfonyl-,    -   (54) —S(O)₂NR^(d)R^(e),    -   (55) —S(O)₂NH(CO)C₁₋₆alkyl,    -   (56) —S(O)₂NH(CO)aryl,    -   (57) —S(O)₂NH(CO)OR^(e), and    -   (58) —S(O)₂NR^(d)SO₂R^(e),        wherein alkyl, alkenyl, alkynyl, and cycloalkyl are optionally        substituted with one, two, or three substituents independently        selected from R^(a), and cycloheteroalkyl, aryl and heteroaryl        are optionally substituted with one, two, or three substituents        independently selected from R^(b).

In one class of this embodiment, R¹ is selected from:

-   -   (1) C₁₋₆alkyl,    -   (2) cyano,    -   (3) C₁₋₆alkylcarbonyl,    -   (4) cycloalkylcarbonyl,    -   (5) cycloheteroalkylcarbonyl,    -   (6) cycloheteroalkyl-C₁₋₄ alkylcarbonyl,    -   (7) arylcarbonyl,    -   (8) heteroarylcarbonyl,    -   (9) aryl-C₁₋₄alkylcarbonyl,    -   (10) heteroaryl-C₁₋₄alkylcarbonyl-,    -   (11) C₁₋₆alkyloxycarbonyl,    -   (12) trifluoromethyloxycarbonyl,    -   (13) cycloalkyloxycarbonyl,    -   (14) cycloalkyl-C₁₋₄alkyloxycarbonyl,    -   (15) cycloheteroalkyloxycarbonyl,    -   (16) cycloheteroalkyl-C₁₋₄ alkyloxycarbonyl;    -   (17) aryloxycarbonyl,    -   (18) heteroaryloxycarbonyl,    -   (19) aryl-C₁₋₄alkyloxycarbonyl,    -   (20) heteroaryl-C₁₋₄alkyloxycarbonyl,    -   (21) —CONR^(d)R^(e),    -   (22) C₁₋₆alkylsulfonyl-,    -   (23) cycloalkylsulfonyl-,    -   (24) cycloalkyl-C₁₋₄alkysulfonyl-,    -   (25) cycloheteroalkylsulfonyl-,    -   (26) cycloheteroalkyl-C₁₋₄ alkylsulfonyl-,    -   (27) arylsulfonyl-,    -   (28) heteroarylsulfonyl-,    -   (29) aryl-C₁₋₄alkylsulfonyl-,    -   (30) heteroaryl-C₁₋₄alkylsulfonyl-,    -   (31) C₁₋₆allyloxysulfonyl-,    -   (32) trifluoromethyloxysulfonyl-,    -   (33) cycloalkyloxysulfonyl-,    -   (34) cycloheteroalkyloxysulfonyl-,    -   (35) aryloxysulfonyl-,    -   (36) heteroaryloxysulfonyl-,    -   (37) S(O)₂NR^(d)R^(e),    -   (38) S(O)₂NH(CO)C₁₋₆alkyl,    -   (39) —(O)₂NH(CO)aryl, and    -   (40) —S(O)₂NR^(d)SO₂R^(e),        wherein alkyl, and cycloalkyl are optionally substituted with        one, two, or three substituents independently selected from        R^(a), and cycloheteroalkyl, aryl and heteroaryl are optionally        substituted with one or two substituents independently selected        from R^(b).

In one subclass of this class, R¹ is selected from:

-   -   (1) C₁₋₆alkyl,    -   (2) cyano,    -   (3) C₁₋₆alkylcarbonyl,    -   (4) cycloalkylcarbonyl,    -   (5) cycloheteroalkylcarbonyl,    -   (6) phenylcarbonyl,    -   (7) heteroarylcarbonyl,    -   (8) C₁₋₆alkyloxycarbonyl,    -   (9) trifluoromethyloxycarbonyl,    -   (10) cycloalkyloxycarbonyl,    -   (11) —CON(CH₃)₂,    -   (12) —CONH(CH₃),    -   (13) —CONH(CF₃),    -   (14) —CON(CH₂CH₃)₂,    -   (15) —CONH(CH₂CH₃),    -   (16) —CON(CH₃)(CH₂CH₃),    -   (17) —CONH(C(CH₃)₃),    -   (18) —CONH(cyclopropyl),    -   (19) —CON(cyclopropyl)₂,    -   (20) C₁₋₆alkylsulfonyl-,    -   (21) cycloalkylsulfonyl-,    -   (22) cycloheteroalkylsulfonyl-,    -   (23) phenylsulfonyl-,    -   (24) heteroarylsulfonyl-,    -   (25) C₁₋₆alkyloxysulfonyl-,    -   (26) trifluoromethyloxysulfonyl-,    -   (27) cycloalkyloxysulfonyl-,    -   (28) cycloheteroalkyloxysulfonyl-,    -   (29) phenyloxysulfonyl-,    -   (30) heteroaryloxysulfonyl-,    -   (31) S(O)₂NR^(d)R^(e),    -   (32) —(O)₂NH(CO)C₁₋₆alkyl, and    -   (33) —S(O)₂NH(CO)aryl;        wherein alkyl and cycloalkyl are optionally substituted with one        or two substituents independently selected from R^(a), and        cycloheteroalkyl, aryl, and heteroaryl are optionally        substituted with one or two substituents independently selected        from R^(b).

In yet another subclass of this class, R¹ is selected from:

-   (1) t-butyl,-   (2) isobutyl,-   (3) isopropyl,-   (4) 1-hydroxy-1-methyl-ethyl,-   (5) n-propyl,-   (6) 1-hydroxy-2,2-dimethylpropyl,-   (7) phenyl, unsubstituted or substituted with one or two    substituents selected from: halo, methoxy, cyano, trifluoromethyl,    methyl, hydroxy, hydroxycarbonyl, methylcarbonyl, and    methoxycarbonyl,-   (8) heteroaryl selected from pyridinyl, pyrazinyl, pyrimidinyl, and    pyridazinyl, unsubstituted or substituted on a carbon atom with one    or two substituents independently selected from methyl, ethyl,    propyl, halo, trifluoromethyl, hydroxy, methoxy, ethyloxy,    methoxycarbonyl, carboxyl, and hydroxyl,-   (9) cyano,-   (10) methylcarbonyl, unsubstituted or substituted on carbon with one    or two substituents independently selected from hydroxyl, methoxy,    ethyoxy, trifluoromethyloxy, and halo;-   (11) ethylcarbonyl, unsubstituted or substituted with one or two    substituents independently selected from methyl, ethyl, propyl,    halo, trifluoromethyl, hydroxy, methoxy, ethyloxy, methoxycarbonyl,    methylcarbonyloxy, and carboxyl,-   (12) n-propylcarbonyl,-   (13) t-butylcarbonyl,-   (14) isopropylcarbonyl, unsubstituted or substituted with one or two    substituents independently selected from methyl, ethyl, propyl,    halo, trifluoromethyl, hydroxy, methoxy, ethyloxy, methoxycarbonyl,    methylcarbonyloxy-, trifluoromethylcarbonyloxy-, propylcarbonyloxy,    butylcarbonyloxy, cyclopropylcarbonyloxy, carboxyl, and    —OC(O)CH₂OC(O)CH₃,-   (15) cyclopropylcarbonyl-   (16) cyclobutylcarbonyl,-   (17) cyclohexylcarbonyl, unsubstituted or substituted with    substituents independently selected from methyl, ethyl, propyl,    halo, trifluoromethyl, hydroxy, methoxy, ethyloxy, methoxycarbonyl,    carboxyl, and hydroxyl,-   (18) cycloheteroalkylcarbonyl, wherein the cycloheteroalkylmoiety is    an unsaturated, nitrogen-containing mono-, bi-or bridged cyclic ring    having 4 to 10 ring atoms, optionally containing a second heteroatom    selected from carbon, sulfur and oxygen, bonded to the carbonyl    through a ring nitrogen atom and optionally substituted on a ring    carbon or nitrogen atom with one or two substituents independently    selected from: methyl, ethyl, propyl, halo, trifluoromethyl,    hydroxy, methoxy, ethyloxy, methoxy-carbonyl, carboxyl, hydroxyl,    —C(O)O(C₁₋₆ alkyl),-   (19) phenylcarbonyl, wherein the phenyl may be substituted with one    or two substituents independently selected from methyl, ethyl,    propyl, halo, trifluoromethyl, hydroxy, methoxy, ethyloxy,    methoxycarbonyl, carboxyl, cyano, hydroxyl, —NHC(O)CH₃,-   (20) heteroarylcarbonyl selected from pyridinylcarbonyl,    pyrazinylcarbonyl, pyrimidinylcarbonyl, and pyridazinylcarbonyl,    oxazolylcarbonyl, wherein the heteroaryl moiety may be substituted    on a carbon atom with one or two substituents independently selected    from methyl, ethyl, propyl, halo, trifluoromethyl, hydroxy, methoxy,    ethyloxy, methoxycarbonyl, carboxyl, and hydroxyl,-   (21) hydroxycarbonyl,-   (22) methoxycarbonyl,-   (23) ethyloxycarbonyl,-   (24) n-propyloxycarbonyl,-   (25) isopropyloxycarbonyl,-   (26) t-butyloxycarbonyl,-   (27) trifluoromethyloxycarbonyl,-   (28) CON(CH₃)₂,-   (29) —CONH(CH₃),-   (30) —CONH(CF₃),-   (31) —CON(CH₂CH₃)₂,-   (32) —CONH(CH₂CH₃),-   (33) —CONH(cyclopropyl),-   (34) CON(cyclopropyl)₂,-   (35) C₁₋₆alkylsulfonyl-,-   (36) phenylsulfonyl-,-   (37) heteroarylsulfonyl-,-   (38) —(O)₂NR^(d)R^(e),-   (39) —(O)₂NH(CO)C₁₋₆alkyl, and-   (40) —S(O)₂NH(CO)aryl.

In one embodiment of the present invention, R² is selected from:

-   -   (1) hydrogen,    -   (2) —NR⁵R⁶,    -   (3) —COR⁴,    -   (4) C₁₋₆alkyl,    -   (5) aryl,    -   (6) arylC₁₋₆alkyl-,    -   (7) heteroaryl,    -   (8) heteroarylC₁₋₆alkyl-,    -   (9) hydroxyl, and    -   (10) OR^(g),        wherein alkyl, alkenyl, and alkynyl are optionally substituted        with one, two, or three substituents independently selected from        R^(a); and aryl, and heteroaryl are optionally substituted with        one, two, or three substituents independently selected from        R^(b) and cycloheteroalkyl is optionally substituted with one,        two, three or four substituents independently selected from        R^(b) and oxo.

In one class of this embodiment, R² is selected from:

-   -   (1) hydrogen,    -   (2) —NR⁵R⁶,    -   (3) —COR⁴,    -   (4) C₁₋₆alkyl,    -   (5) phenyl,    -   (6) phenylC₁₋₃alkyl-,    -   (7) heteroaryl,    -   (8) heteroarylC₁₋₃alkyl-,    -   (9) cycloheteroalkyl,    -   (10) hydroxyl, and    -   (11) OR^(g),        wherein alkyl is optionally substituted with one, two, or three        substituents independently selected from R^(a); and aryl,        heteroaryl, and cycloheteroalkyl are optionally substituted with        one, two, or three substituents independently selected from        R^(b).

In another class of this embodiment, R² is selected from:

-   -   (1) hydrogen,    -   (2) —NR⁵R⁶,    -   (3) —COR⁴,    -   (4) C₁₋₆alkyl, unsubstituted or substituted with one or two        R^(a) substituents,    -   (5) phenyl, unsubstituted or substituted with one or two R^(b)        substituents,    -   (6) phenylC₁₋₃alkyl-,    -   (7) heteroaryl,    -   (8) heteroarylC₁₋₃alkyl-,    -   (9) cycloheteroalkyl, unsubstituted or substituted on nitrogen,        sulfur or carbon with one, two, three or four substitutents        selected from R^(b) and oxo,    -   (10) hydroxyl, and    -   (11) OR^(g);        wherein alkyl is optionally substituted with one, two, or three        substituents independently selected from R^(a); and phenyl,        heteroaryl, and cycloheteroalkyl are optionally substituted with        one, two, or three substituents independently selected from        R^(b), and heteroaryl is selected from: pyrrolyl, isoxazolyl,        isothiazolyl, pyrazolyl, pyridyl, oxazolyl, oxadiazolyl,        thiadiazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl,        furanyl, triazinyl, thienyl, pyrimidyl, pyridazinyl, pyrazinyl,        benzoxazolyl, benzothiazolyl, benzimidazolyl, benzofuranyl,        benzothiophenyl, benzothiazolyl, quinolyl, indolyl, isoquinolyl,        and oxazolidinyl.

In one subclass of this class, R² is selected from:

-   -   (1) hydrogen,    -   (2) —NR⁵R⁶,    -   (3) —COR⁴,    -   (4) C₁₋₆alkyl, unsubstituted or substituted with one or two        R^(a) substituents,    -   (5) phenyl, unsubstituted or substituted with one or two R^(b)        substituents,    -   (6) phenylC₁₋₃alkyl-,    -   (7) heteroaryl,    -   (8) heteroarylC₁₋₃alkyl-,    -   (9) a nitrogen-linked 5 to 7 membered ring, optionally        containing one other heteroatom selected from nitrogen, sulfur        and oxygen, unsubstituted or substituted on nitrogen, sulfur or        carbon with one, two, three or four substituents selected from        R^(b) and oxo,    -   (10) hydroxyl, and    -   (11) OR^(g);        wherein alkyl is optionally substituted with one or two        substituents independently selected from R^(a); and phenyl is        optionally substituted with one or two substituents        independently selected from R^(b); and heteroaryl is selected        from: pyridinyl, benzimidazolyl, imidazolyl, oxazolidinyl,        pyrimidyl, pyridazinyl, pyrazinyl, triazolyl, and        benzotriazolyl, wherein the heteroaryl may be unsubstituted or        substituted on one or two carbon atoms with R^(b).

In another subclass of this class, R² is selected from:

-   -   (1) —NR⁵R⁶,    -   (2) —COR⁴,    -   (3) C₁₋₆alkyl, unsubstituted or substituted with one or two        R^(a) substituents.    -   (4) phenyl, unsubstituted or substituted with one or two R^(b)        substituents,    -   (5) benzyl, unsubstituted or substituted with one or two R^(b)        substituents,    -   (6) heteroaryl selected from: pyridinyl, benzimidazolyl,        imidazolyl, oxazolidinyl, triazolyl, and benzotriazolyl, wherein        the heteroaryl may be unsubstituted or substituted on one or two        carbon atoms with R^(b),    -   (7) heteroarylmethyl selected from: pyridinylmethyl,        benzimidazolylmethyl, imidazolylmethyl, oxazolidinymethyll,        triazolylmethyl, and benzotriazolylmethyl, wherein the        heteroaryl may be unsubstituted or substituted on one or two        carbon atoms with R^(b),    -   (8) cycloheteroalkyl selected from: azetidinyl, pyrrolidinyl,        piperidinyl, piperazinyl, imidazolidinyl, morpholinyl,        dihydroisoindolyl, pyranyl, perhydroazepinyl, tetrahydrofuranyl,        dioxanyl, oxanyl, 1-thia-4-aza-cyclohexane (thiomorpholinyl),        2,5-diazabicyclo[2.2.2]octanyl, benzoxazinyl,        tetrahydroquinolinyl, tetrahydroisoquinolinyl, dihydroindolyl,        dihydroisoindolyl, indolyl, indolinyl, isoindolinyl,        isothiazolindinyl, 1,3-dihydro-2-benzofuranyl, benzodioxolyl,        hexahydrothienopyridinyl, thienopyridinyl, azacycloheptyl,        azabicyclo[3.1.0]hexyl, 2-oxa-5-azabicyclo[2.2.1]heptyl,        2,5-diazabicyclo[2.2.1]heptyl, 2-azabicyclo[2.2.1]heptyl,        7-azabicyclo[2.2.1.]heptyl, 2,4-dizaobicyclo[2.2.2]octyl,        2-azabicyclo[2.2.2]octyl, 3-azabicyclo[3.2.2]nonyl, 2H-pyrrolyl,        4,4-spiro[2,3-dihydrobenzothiophen-3,3-yl]piperidinyl,        4,4-spiro[indoli-3,3-yl]piperidinyl, either unsubstituted or        substituted on a nitrogen, sulfur or carbon atom with a        substituent selected from R^(b) and oxo,    -   (9) hydroxyl, and    -   (10) OR^(g) wherein R^(g) is selected from alkyl and        alkylcarbonyl, either unsubstituted or substituted with one, two        or three R^(a) substituents.

In yet another subclass of this class, R² is selected from:

-   -   (1) hydrogen,    -   (2) —NR⁵R⁶,    -   (3) —COR⁴,    -   (4) C₁₋₆alkyl, unsubstituted or substituted with one or two        R^(a) substituents,    -   (5) phenyl, unsubstituted or substituted with one or two R^(b)        substituents,    -   (6) benxyl, unsubstituted or substituted with one or two R^(b)        substituents,    -   (7) heteroaryl,    -   (8) heteroaryl methyl,    -   (9) cycloheteroalkyl selected from: azetidinyl, pyrrolidinyl,        piperidinyl, imidazolidinyl, morpholinyl,        1-thia-4-azacyclohexyl, azacycloheptyl, isothiazolidinyl,        azabicyclo[3.1.0]heptane, either unsubstituted or substituted on        a nitrogen, sulfur or carbon atom with a substituent selected        from R^(b) and oxo,    -   (10) hydroxyl, and    -   (11) —OR^(g) wherein R^(g) is selected from alkyl and        alkylcarbonyl, either unsubstituted or substituted with one or        two R^(a) substituents, wherein heteroaryl is selected from:        pyridinyl, benzimidazolyl, pyrazinyl, imidazolyl, oxazolidinyl,        triazolyl, and benzotriazolyl., wherein the heteroaryl may be        unsubstituted or substituted on one or two carbon atoms with        R^(b).

In another embodiment of the present invention, R³ is selected from:

-   -   (1) hydrogen,    -   (2) methyl,    -   (3) ethyl,    -   (4) propyl,    -   (5) t-butyl,    -   (6) methoxy,    -   (7) ethyloxy,    -   (8) propyloxy,    -   t-butyloxy,    -   (10) trifluoromethyloxy,    -   (11) trifluoromethyl,    -   (12) halo, and    -   (13) cyclopropyl,    -   wherein the alkyl and cycloalkyl moieties are optionally        substituted with one or two substituents independently selected        from R^(a).

In one class of this embodiment, the alkyl and cycloalkyl moieties areoptionally substituted with one or two substituents independentlyselected from: halo, trifluoromethyl, methoxy, ethyloxy,methoxycarbonyl, and carboxyl.

In another class, R³ is selected from:

-   -   (1) hydrogen,    -   (2) methyl,    -   (3) trifluoromethyl,    -   (4) methoxy,    -   (5) trifluoromethyloxy,    -   (6) chloro, and    -   (7) fluoro.

In a subclass of this class, R³ is hydrogen.

In one embodiment of the present invention, R⁴ is selected from:

-   -   (1) hydrogen,    -   (2) C₁₋₆alkyl,    -   (3) cycloalkyl,    -   (4) cycloalkyl-C₁₋₃alkyl;    -   (5) cycloheteroalkyl,    -   (6) cycloheteroalkyl-C₁₋₃ alkyl;    -   (7) aryl,    -   (8) heteroaryl,    -   (9) aryl-C₁₋₃alkyl, and    -   (10) heteroaryl-C₁₋₃alkyl-,    -   (11) —OR^(e),    -   (12) —NR^(d)R^(e),    -   (13) —NH(CO)R^(e), and    -   (14) —NR^(d)SO₂R^(e),        wherein alkyl, and cycloalkyl are optionally substituted with        one, two, or three substituents independently selected from        R^(a), and cycloheteroalkyl, aryl and heteroaryl are optionally        substituted with one, two, or three substituents independently        selected from R^(b).

In one class of this embodiment, R⁴ is selected from:

-   -   (1) hydrogen,    -   (2) C₁₋₆alkyl,    -   (3) cycloalkyl,    -   (4) cycloheteroalkyl,    -   (5) phenyl,    -   (6) heteroaryl,    -   (7) aryl-C₁₋₃alkyl,    -   (8) heteroaryl-C₁₋₃alkyl-,    -   (9) —OR^(e),    -   (10) —NR^(d)R^(e),    -   (11) —NH(CO)OR^(e), and    -   (12) —NHSO₂R^(e),        wherein alkyl and cycloalkyl are optionally substituted with one        or two substituents independently selected from R^(a), and        cycloheteroalkyl, aryl and heteroaryl are optionally substituted        with one or two substituents independently selected from R^(b).

In one subclass of this class, R⁴ is selected from:

-   -   (1) methyl,    -   (2) ethyl, unsubstituted or substituted with one or two        substituents selected from halo, OR^(e), and —OC(O)R^(c),    -   (3) isopropyl, unsubstituted or substituted with one or two        substituents from halo, OR^(e), and —OC(O)R^(c),    -   (4) n-propyl, unsubstituted or substituted with one or two        substituents selected from halo, OR^(e), and —OC(O)R^(c),    -   (5) t-butyl, unsubstituted or substituted with one or two        substituents selected from from halo, OR^(e), and —OC(O)R^(c),    -   (6) cyclopropyl,    -   (7) cyclobutyl,    -   (8) cyclopentyl,    -   (9) cyclohexyl,    -   (10) phenyl, unsubstituted or substituted with one or two        substituents selected from halo, methyl, trifluoromethyl,        methoxy, methoxycarbonyl, —NHC(O)R^(c), and carboxyl,    -   (11) phenyl-C₁₋₃alkyl, wherein the alkyl moiety is unsubsituted        or substituted with a substituent selected from: halo, methyl,        trifluoromethyl, methoxy, methoxy carbonyl, carboxyl, and        —NHC(O)R^(c),    -   (12) heteroaryl selected from furanyl, pyridyl and imidazolyl,        unsubstituted or substituted with one or two substituents        selected from halo, methyl, trifluoromethyl, methoxy,        methoxycarbonyl, and carboxyl,    -   (13) cycloheteroalkyl, selected from morpholinyl, piperidinyl,        pyrrolidinyl, piperazinyl, imidazolidinyl, azetidinyl,        azabicyclo[3.1.0]hexyl, and isothiazolidinyl, unsubstituted or        substituted with methyl or —CO₂R^(c),    -   (14) methoxy,    -   (15) ethyloxy,    -   (16) t-butyloxy,    -   (17) isopropyloxy, and    -   (18) —NR^(d)R^(e).

In one embodiment of the present invention, R⁵ is selected from:

-   -   (1) hydrogen,    -   (2) C₁₋₄alkyl,    -   (3) C₂₋₄alkenyl,    -   (4) phenyl,    -   (5) cycloalkyl,    -   (6) trifluoromethyl,    -   (7) methylcarbonyl-,    -   (8) methoxycarbonyl-,    -   (9) t-butyloxycarbonyl,    -   (10) hydroxycarbonyl-,    -   (11) —C(O)C(O)OR^(c),    -   (12) —C(O)C(O)NR^(e)R^(f),    -   (13) —S(O)₂R^(c), and    -   (14) —C(O)N(R^(d))S(O)_(m)R^(c),        wherein alkyl, alkenyl, and cycloalkyl may optionally be        substituted with one or two R^(a) substituents, and phenyl may        be substituted with one or two R^(b) substituents.

In one class of this embodiment, R⁵ is selected from:

-   -   (1) hydrogen,    -   (2) C₁₋₄alkyl, unsubstituted or substituted with hydroxyl,    -   (3) C₂₋₄alkenyl,    -   (4) phenyl,    -   (5) cyclopropyl,    -   (6) cyclopentyl,    -   (7) cyclohexyl,    -   (8) trifluoromethyl,    -   (9) methylcarbonyl-,    -   (10) methoxycarbonyl-,    -   (11) t-butyloxycarbonyl,    -   (12) hydroxycarbonyl-,    -   (13) —S(O)₂CH₃    -   (14) —S(O)₂CH₂CH₂Cl, and    -   (15) 4-methylphenylsulfonyl.

In one subclass of this class, R⁵ is selected from:

-   -   (1) hydrogen,    -   (2) methyl,    -   (3) ethyl,    -   (4) hydroxyethyl,    -   (5) propenyl,    -   (6) trifluoromethyl,    -   (7) methylcarbonyl,    -   (8) t-butyloxycarbonyl,    -   (9) —S(O)₂CH₃,    -   (10) —S(O)₂CH₂CH₂Cl, and    -   (11) paramethylphenylsulfonyl.

In one embodiment of the present invention, R⁶ is selected from:

-   -   (1) hydrogen,    -   (2) C₁₋₆alkyl,    -   (3) C₂₋₆alkenyl,    -   (4) trifluoromethyl,    -   (5) phenyl,    -   (6) cycloalkyl,    -   (7) —C(O)—R^(c),    -   (8) —CO₂R^(c),    -   (9) —C(O)C(O)OR^(c),    -   (10) —C(O)C(O)NR^(e)R^(f),    -   (11) —(O)₂R^(c), and    -   (12) —C(O)N(R^(d))S(O)_(r)R^(c),        wherein alkyl, alkenyl, alkynyl, and cycloalkyl may be        optionally substituted with one or two R^(a) substituents, and        aryl may be optionally substituted with one or two R^(b)        substituents.

In one class of this embodiment, R⁶ is selected from:

-   -   (1) hydrogen,    -   (2) C₁₋₆alkyl,    -   (3) C₂₋₆alkenyl,    -   (4) trifluoromethyl,    -   (5) —C(O)—R^(c),    -   (6) —CO₂R^(c),    -   (7) —C(O)C(O)OR^(c),    -   (8) —C(O)C(O)NR^(e)R^(f),    -   (9) —S(O)₂R^(c) and    -   (10) —C(O)NHS(O)₂R^(c),        wherein R^(c) is selected from the group consisting of:    -   (1) hydrogen,    -   (2) C₁₋₆alkyl,    -   (3) phenyl,    -   (4) cyclopropyl,    -   (5) cyclopentyl,    -   (6) cyclohexyl,    -   (7) trifluoromethyl,    -   —NR^(d)R^(d), wherein each R^(d) is independently selected from        hydrogen, trifluoromethyl, hydroxyC₁₋₆alkyl, arylsulfonyl,        C₁₋₁₀alkylsulfonyl, and C₁₋₆alkyll, wherein the alkyl and aryl        groups may be unsubstituted or substituted with one, two or        three substituents independently selected from R^(h);        wherein each alkyl, phenyl, and cycloalkyl is unsubstituted or        substituted with an R^(h) substituent.

In one subclass of this class, R⁶ is selected from:

-   -   (1) hydrogen,    -   (2) methyl, unsubstituted or substituted with one or two        substituents independently selected from halogen, hydroxy,        amino, dimethylamino, methylamino, aminocarbonyl,        dimethylaminocarbonyl, and methylaminocarbonyl,    -   (3) ethyl, unsubstituted or substituted with one or two        substituents independently selected from halogen, hydroxy,        amino, dimethylamino, methylamino, aminocarbonyl,        dimethylaminocarbonyl, and methylaminocarbonyl,    -   (4) t-butyl, unsubstituted or substituted with one or two        substituents independently selected from halogen, hydroxy,        amino, dimethylamino, methylamino, aminocarbonyl,        dimethylaminocarbonyl, and methylaminocarbonyl,    -   (5) phenyl,    -   (6) trifluoromethyl,    -   (7) methylcarbonyl, unsubstituted or substituted with one, two        or three R_(h) substituents,    -   (8) ethylcarbonyl, unsubstituted or substituted with one or two        halo or hydroxy substituents, 1    -   (9) n-propylcarbonyl, unsubstituted or substituted with one or        two halo or hydroxy substituents,    -   (10) isopropylcarbonyl, unsubstituted or substituted with one or        two halo or hydroxy substituents,    -   (11) t-butylcarbonyl, unsubstituted or substituted with one or        two halo or hydroxy substituents,    -   (12) n-butylcarbonyl, unsubstituted or substituted with one or        two halo or hydroxy substituents,    -   (13) trifluoromethylcarbonyl,    -   (14) methoxycarbonyl,    -   (15) ethyloxycarbonyl,    -   (16) t-butyloxycarbonyl,    -   (17) trifluoromethoxycarbonyl, and    -   (18) —S(O)₂R^(c);        wherein R^(c) is selected from the group consisting of:    -   (1) C₁₋₄alkyl,    -   (2) trifluoromethyl,    -   (3) —NR^(d)R^(d), wherein each R^(d) is independently selected        from hydrogen, trifluoromethyl, arylsulfonyl,        C₁₋₁₀alkylsulfonyl, and C₁₋₄alkyl, unsubstituted or substituted        with one, two or three R^(h) substituents,

In one subclass of this class, R⁶ is selected from:

-   -   (1) hydrogen,    -   (2) methyl,    -   (3) ethyl,    -   (4) t-butyl,    -   (5) trifluoromethyl,    -   (6) methylcarbonyl,    -   (7) ethylcarbonyl, unsubstituted or substituted with one or two        halo or hydroxy substituents,    -   (8) n-propylcarbonyl, unsubstituted or substituted with one or        two halo or hydroxy substituents,    -   (9) isopropylcarbonyl, unsubstituted or substituted with one or        two halo or hydroxy substituents,    -   (10) t-butylcarbonyl, unsubstituted or substituted with one or        two halo or hydroxy substituents,    -   (11) n-butylcarbonyl, unsubstituted or substituted with one or        two halo or hydroxy substituents,    -   (12) trifluoromethylcarbonyl,    -   (13) methoxycarbonyl,    -   (14) ethyloxycarbonyl,    -   (15) t-butyloxycarbonyl,    -   (16) trifluoromethoxycarbonyl,    -   (17) —(O)₂NH₂, and    -   (18) —(O)₂CH₃.

In another embodiment of the present invention, R⁵ and R⁶ together form═CH—N(R^(e))(R^(f)). In one class of this embodiment, R⁵ and R⁶ togetherform ═CH—N(CH₃)₂.

In one embodiment of the present invention, Ar¹ is selected from:

-   -   (1) phenyl, and    -   (2) pyridyl;        wherein phenyl and pyridyl are optionally substituted with one        or two R^(b) substituents.

In one class of this embodiment of the present invention, Ar¹ isselected from:

-   -   (1) phenyl, and    -   (2) pyridyl;        wherein phenyl and pyridyl are optionally substituted with one        or two halogen, methyl, methoxy, trifluoromethyl or cyano        substituents.

In a subclass of this class of the present invention, Ar¹ is phenyl,2-chlorophenyl, 2,4-dichlorophenyl, 2-fluorophenyl, 2-bromophenyl,2-iodophenyl, 2-cyanophenyl, 3,4-dichlorophenyl,3-methyl-4-chlorophenyl, 4-chlorophenyl, 4-fluorophenyl, 4-iodophenyl,4-methylphenyl, or 4-methoxyphenyl.

In another subclass of this class, Ar¹ is 4-chlorophenyl.

In another embodiment of the present invention, Ar² is selected from:

-   -   (1) aryl, and    -   (2) heteroaryl;        wherein aryl and heteroaryl are optionally substituted with one        or two R^(b) substituents.

In one class of this embodiment of the present invention, Ar² isselected from:

-   -   (1) phenyl,    -   (2) 1,3-benzodioxolyl, and    -   (3) pyridyl; wherein phenyl and pyridyl are optionally        substituted with one or two R^(b) substituents.

In one subclass of this class of the invention, Ar² is selected from:

-   -   (1) phenyl, and    -   (2) pyridyl,        wherein phenyl and pyridyl are optionally substituted with one        or two halogen, methyl, methoxy, trifluoromethyl or cyano        substituents.

In another subclass of this class, Ar² is selected from: phenyl,1,3-benzodioxol-5-yl, 2,4-dichlorophenyl, 2-chlorophenyl,2-chloro-4-fluorophenyl, 2-chloro-4-bromophenyl, 2-chloro-4-cyanophenyl,2-chloro-4-methoxyphenyl, 4-chlorophenyl, 2-fluorophenyl,2,4-di-iodophenyl, 1-bromophenyl, 3-bromophenyl, 2-bromo-4-chlorophenyl,2-iodophenyl, 4-iodophenyl, 2-cyanophenyl, 2-cyano-4-chlorophenyl,2-methoxyphenyl, and 3-pyridyl.

In still another subclass of this class, Ar² is 2,4-dichlorophenyl or2-chlorophenyl.

In one embodiment of the present invention, each R^(a) is independentlyselected from:

-   -   (1) —OR^(e),    -   (2) —NHS(O)_(m)R^(c),    -   (3) halogen,    -   (4) —S(O)₂R^(c),    -   (5) —SR^(e),    -   (6) —S(O)₂OR^(e),    -   (7) —S(O)₂NR^(e)R^(f),    -   (8) —NR^(e)R^(f),    -   (9) —O(CH₂)_(n)NR^(e)R^(f),    -   (10) —C(O)R^(c),    -   (11) —CO₂R^(c),    -   (12) —CO₂(CH₂)_(n)CONR^(e)R^(f),    -   (13) —OC(O)R^(c),    -   (14) —CN,    -   (15) —C(O)NHR^(f),    -   (16) —NHC(O)R^(c),    -   (17) —NHC(O)OR^(e),    -   (18) —NHC(O)NHR^(e),    -   (19) —CH(N—OR^(e)),    -   (20) CF₃,    -   (21) —OCF₃,    -   (22) C₃₋₈cycloalkyl, and    -   (23) cycloheteroalkyl.

In one class of this embodiment of the present invention, each R^(a) isindependently selected from:

-   -   (1) —OR^(e),    -   (2) halogen,    -   (3) —S(O)₂R^(c),    -   (4) —SR^(e),    -   (5) —S(O)₂OR^(e),    -   (6) —S(O)₂NR^(e)R^(f),    -   (7) —NR^(e)R^(f),    -   (8) —C(O)R^(c),    -   (9) —CO₂R^(c),    -   (10) —OC(O)R^(c),    -   (11) —CN,    -   (12) —CH(N—OR^(e)),    -   (13) CF₃,    -   (14) —OCF₃,    -   (15) C₃₋₈cycloalkyl, and    -   (16) cycloheteroalkyl.

In a subclass of this class, each R^(a) is independently selected from:

-   -   (1) hydroxyl,    -   (2) methoxy,    -   (3) ethyloxy,    -   (4) halogen,    -   (5) —NH₂    -   (6) —NHCH₃    -   (7) —N(CH₃)₂    -   (8) —C(O)R^(c),    -   (9) —CO₂R^(c),    -   (10) O—C(O)R^(c),    -   (11) CF₃, and    -   (12) —OCF₃.

In one embodiment of the present invention, each R^(b) is independentlyselected from:

-   -   (1) —OR^(e),    -   (2) —NHS(O)_(m)R^(c),    -   (3) —NO₂,    -   (4) halogen,    -   (5) —S(O)₂R^(c),    -   (6) —SR^(e),    -   (7) —S(O)₂OR^(e),    -   (8) —S(O)₂NHR^(f),    -   (9) —NR^(e)R^(f),    -   (10) —O(CH₂)_(n)NR^(e)R^(f),    -   (11) —C(O)R^(c),    -   (12) —CO₂R^(c),    -   (13) —CO₂(CR^(e)R^(f))_(n)CONR^(e)R^(f),    -   (14) —OC(O)R^(c),    -   (15) —CN,    -   (16) —C(O)NHR^(f),    -   (17) —NHC(O)R^(c),    -   (18) —NHC(O)OR^(e),    -   (19) —NHC(O)NR^(d)R^(e),    -   (20) —CH(N—OR^(e)),    -   (21) CF₃,    -   (22) —OCF₃,    -   (23) C₃₋₈cycloalkyl, and    -   (24) cycloheteroalkyl;    -   (25) C₁₋₁₀alkyl,    -   (26) aryl,    -   (27) arylC₁₋₄alkyl,    -   (28) heteroaryl, and    -   (29) heteroarylC₁₋₄alkyl,        wherein each aryl and heteroaryl is unsubstituted or substituted        with one or two R^(h) substituents.

In one class of this embodiment of the present invention, each R^(b) isindependently selected from:

-   -   (1) —OR^(e),    -   (2) halogen,    -   (3) —S(O)₂R^(c),    -   (4) —SR^(e),    -   (5) —S(O)₂OR^(e),    -   (6) —S(O)₂NHR^(f),    -   (7) —NR^(e)R^(f),    -   (8) —C(O)R^(c),    -   (9) —CO₂R^(c),    -   (10) —CN,    -   (11) —CH(N—OR^(e)),    -   (12) CF₃,    -   (13) —OCF₃,    -   (14) C₃₋₈cycloalkyl,    -   (15) cycloheteroalkyl;    -   (16) C₁₋₄alkyl,    -   (17) aryl,    -   (18) arylC₁₋₄alkyl,    -   (19) heteroaryl, and    -   (20) heteroarylC₁₋₄alkyl, wherein each aryl and heteroaryl is        unsubstituted or substituted with one or two R^(h) substituents.

In a subclass of this class, each R^(b) is independently selected from:

-   -   (1) —OR^(e),    -   (2) halogen,    -   (3) —S(O)₂R^(c),    -   (4) —SH,    -   (5) —SCH₃,    -   (6) —NR^(e)R^(f),    -   (7) —C(O)R^(c),    -   (8) —CO₂R^(c),    -   (9) —CN,    -   (10) CF₃,    -   (11) —OCF₃,    -   (12) C₃₋₈cycloalkyl,    -   (13) cycloheteroalkyl;    -   (14) C₁₋₄alkyl,    -   (15) phenyl,    -   (16) benzyl,    -   (17) heteroaryl, and    -   (18) heteroarylmethyl,        wherein each aryl and heteroaryl is unsubstituted or substituted        with one or two R^(h) substituents.

In another subclass, each R^(b) is independently selected from:

-   -   (1) methoxy,    -   (2) halogen,    -   (3) —SH,    -   (4) —SCH₃,    -   (5) —NH₂,    -   (6) —C(O)CH₃,    -   (7) —CO₂CH₃,    -   (8) —CO₂H,    -   (9) —CN,    -   (10) CF₃,    -   (11) —OCF₃,    -   (12) C₃₋₆cycloalkyl,    -   (13) C₁₋₄alkyl,    -   (14) phenyl,    -   (15) benzyl, and    -   (16) heteroaryl,        wherein each aryl and heteroaryl is unsubstituted or substituted        with one or two R^(h) substituents.

In still another subclass of this class, each R^(b) is independentlyselected from halogen, methyl, ethyl, hydroxy, methoxy, trifluoromethyl,cyano, methylcarbonylamino, and t-butyloxycarbonyl.

In one embodiment of the present invention, each R^(c) is independentlyselected from:

-   -   (1) hydrogen,    -   (2) C₁₋₆alkyl,    -   (3) C₁₋₇ perfluoromethyl,    -   (4) cycloalkyl,    -   (5) cycloalkyl-C₁₋₄alkyl,    -   (6) cycloheteroalkyl,    -   (7) cycloheteroalkyl-C₁₋₄ alkyl,    -   (8) phenyl,    -   (9) heteroaryl,    -   (10) phenyl-C₁₋₄alkyl,    -   (11) heteroaryl-C₁₋₄alkyl, and    -   (12) —NR^(d)R^(d);        wherein alkyl, cycloalkyl, cycloheteroalkyl, phenyl, and        heteroaryl may be substituted with one or two R^(h)        substituents, and alkyl, cycloalkyl, cycloheteroalkyl may be        substituted on a carbon or sulfur atom with one or two oxo        substituents.

In one class of this embodiment of the present invention, each R^(c) isindependently selected from:

-   -   (1) hydrogen,    -   (2) C₁₋₆alkyl,    -   (3) C₁₋₇ perfluoromethyl,    -   (4) cycloalkyl,    -   (5) cycloheteroalkyl,    -   (6) cycloheteroalkylC₁₋₃ alkyl,    -   (7) phenyl,    -   (8) phenylC₁₋₃ alkyl,    -   (9) heteroaryl,    -   (10) heteroarylC₁₋₃ alkyl, and    -   (11) —NR^(d)R^(d);        wherein alkyl, cycloalkyl, cycloheteroalkyl, phenyl, and        heteroaryl may be substituted with an R^(h) substituent and        alkyl, cycloalkyl, cycloheteroalkyl may be substituted on a        carbon or sulfur atom with one or two oxo substituents.

In one subclass of this class, each R^(c) is independently selectedfrom:

-   -   (1) C₁₋₄alkyl, unsubstituted or substituted with one or two        R^(h) substituents,    -   (2) C₁₋₇ perfluoromethyl,    -   (3) cyclopropyl,    -   (4) cycloheteroalkyl, selected from morpholinyl, azetidinyl,        pyrrolidinyl, piperidinyl, imidazolidinyl, substituted with one        or two substituents independently selected from oxo and R^(h),    -   (5) cycloheteroalkylC₁₋₃ alkyl, wherein the cycloheteroaryl        moiety is selected from morpholinyl, azetidinyl, pyrrolidinyl,        piperidinyl, imidazolidinyl, unsubstituted or substituted with        one or two substituents independently selected from oxo and        R^(h),    -   (6) phenyl, unsubstituted or substituted with one or two R^(h)        substituents,    -   (7) benzyl,    -   (8) heteroaryl C₁₋₃ alkyl, wherein the heteroaryl moiety is        selected from pyridinyl, furanyl and imidazolyl, and the        heteroaryl may be substituted with one or two R^(h)        substituents, and    -   (9) —NR^(d)R^(d).

In another subclass, each R^(c) is independently selected from:

-   -   (1) methyl, unsubstituted or substituted with a halo or hydroxy        substituent,    -   (2) ethyl, unsubstituted or substituted with a halo or hydroxy        substituent,    -   (3) n-propyl, unsubstituted or substituted with a halo or        hydroxy substituent,    -   (4) isopropyl, unsubstituted or substituted with a halo or        hydroxy substituent,    -   (5) t-butyl, unsubstituted or substituted with a halo or hydroxy        substituent,    -   (6) trifluoromethyl,    -   (7) —NH₂,    -   (8) —N(CH₃)₂, and    -   (9) —NHCH₃.

In one embodiment of the present invention, each R^(d) is independentlyselected from: hydrogen, C₁₋₁₀alkyl, and C₁₋₁₀alkylcarbonyl-,arylsulfonyl, C₁₋₁₀alkylsulfonyl, wherein the alkyl and aryl groups maybe unsubstituted or substituted with one, two or three substituentsindependently selected from R^(h).

In one class of this embodiment, each R^(d) is independently selectedfrom:

-   -   (1) hydrogen,    -   (2) C₁₋₆ alkyl, unsubstituted or substituted with one to three        substituents selected from halogen and hydroxyl, and    -   (3) phenylsulfonyl, unsubstituted or substituted on phenyl with        one or two halogen substituents.

In a subclass of this class, each R^(d) is independently selected from:

-   -   (1) hydrogen,    -   (2) C₁₋₄ alkyl,    -   (3) hydroxyl-C₁₋₄ alkyl,    -   (4) trifluoromethyl, and    -   (5) 4-chlorosulfonyl.

In another subclass of this class, each R^(d) is independently selectedfrom hydrogen, methyl, trifluoromethyl, 2-hydroxyethyl, andparachlorosulfonyl.

In one embodiment of the present invention, each R^(e) is independentlyselected from: hydrogen, C₁₋₆alkyl, trifluoromethyl, cycloalkyl,cycloalkyl-C₁₋₄ alkyl, cycloheteroalkyl, cycloheteroalkyl-C₁₋₄ alkyl,phenyl, heteroaryl, phenyl-C₁₋₄ alkyl, and heteroaryl-C₁₋₄ alkyl at eachoccurrence, either unsubstituted or substituted on a carbon or nitrogenatom with one, two or three substituents selected from R^(h).

In one class of this embodiment, each R^(e) is independently selectedfrom: hydrogen, C₁₋₆alkyl, trifluoromethyl, cycloalkyl, cycloalkyl-C₁₋₁₂alkyl, cycloheteroalkyl, cycloheteroalkyl-C₁₋₂ alkyl, phenyl,heteroaryl, benzyl, and heteroaryl-C₁₋₂ alkyl at each occurrence, eitherunsubstituted or substituted on a carbon or nitrogen atom with one, ortwo selected from R^(h).

In one subclass, each R^(e) is independently selected from: hydrogen,C₁₋₄alkyl, trifluoromethyl, cyclopropyl, cyclopentyl, cyclohexyl,phenyl, pyridyl, pyridinyl, pyrazinyl, pyridazinyl, benzyl, andpyridylmethyl, pyrazinylmethyl, and pyridazinylmethyl at eachoccurrence, either unsubstituted or substituted on a carbon or nitrogenatom with one or two substituents selected from R^(h).

In yet another subclass, each R^(e) is independently selected fromhydrogen and C₁₋₄ alkyl.

In one embodiment of the present invention, each R^(f) is independentlyselected from: hydrogen, C₁₋₆alkyl, trifluoromethyl, cycloalkyl,cycloalkyl-C₁₋₄ alkyl, cycloheteroalkyl, cycloheteroalkyl-C₁₋₄ alkyl,phenyl, heteroaryl, phenyl-C₁₋₄ alkyl, and heteroaryl-C₁₋₄ alkyl at eachoccurrence, either unsubstituted or substituted on a carbon or nitrogenatom with one, two or three substituents selected from R^(h).

In one class of this embodiment, each R^(f) is independently selectedfrom: hydrogen, C₁₋₆alkyl, trifluoromethyl, cycloalkyl, cycloalkyl-C₁₋₁₂alkyl, cycloheteroalkyl, cycloheteroalkyl-C₁₋₂ alkyl, phenyl,heteroaryl, benzyl, and heteroaryl-C₁₋₂ alkyl at each occurrence eitherunsubstituted or substituted on a carbon or nitrogen atom with one, ortwo selected from R^(h).

In one subclass, each R^(f) is independently selected from: hydrogen,C₁₋₄alkyl, trifluoromethyl, cyclopropyl, cyclopentyl, cyclohexyl,cycloheteroalkyl, phenyl, pyridyl, pyridinyl, pyrazinyl, pyridazinyl,benzyl, pyridylmethyl, pyridinylmethyl, pyrazinylmethyl, andpyridazinylmethyl at each occurrence, either unsubstituted orsubstituted on a carbon or a cycloheteroalkyl nitrogen atom with one ortwo substituents selected from R^(h).

In yet another subclass, each R^(f) is independently selected fromhydrogen and C₁₋₄alkyl.

In yet another embodiment of the present invention, R^(e) and R^(f) arebonded to the same atom, and together with the atom to which they areattached form a ring of 5 to 7 members containing 0, 1, or 2 heteroatomsindependently selected from oxygen, sulfur and nitrogen, unsubstitutedor substituted on a carbon or nitrogen atom with one or two or threesubstituents selected from R^(h).

In one class of this embodiment, R^(e) and R^(f), together with the atomto which they are attached form a ring selected from: pyrrolidinyl,piperidinyl, morpholinyl, 1-thia-4-azacyclohexyl, azacycloheptyl,unsubstituted or substituted on a carbon or nitrogen atom with one ortwo or three substituents selected from R^(h).

In one subclass, R^(e) and R^(f), together with the atom to which theyare attached form a ring selected from: pyrrolidinyl, piperidinyl,morpholinyl, 1-thia-4-azacyclohexyl, and azacycloheptyl.

In one embodiment of the present invention, R^(g) is selected from:

-   -   (1) C₁₋₆alkyl,    -   (2) C₁₋₆alkylcarbonyl-,    -   (3) phenyl,    -   (4) phenylcarbonyl, and    -   (5) C₁₋₆alkylsulfonyl-, and    -   (6) phenylsulfonyl,        wherein each alkyl may be unsubstituted or substituted with one        or two R^(a) substituents, and each phenyl may be unsubstituted        or substituted with one or two R^(b) substituents.

In one class of this embodiment, R^(g) is selected from:

-   -   (1) C₁₋₆alkyl,    -   (2) methylcarbonyl-,    -   (3) phenyl,    -   (4) phenylcarbonyl,    -   (5) methylsulfonyl, and    -   (6) phenylsulfonyl,        wherein each alkyl may be unsubstituted or substituted with an        R^(a) substituent, and each phenyl may be unsubstituted or        substituted with one or two R^(b) substituents.

In one subclass of this class, R^(g) is selected from alkyl andalkylcarbonyl, either unsubstituted or substituted with cyano, carboxyl,or amide.

In one embodiment of the present invention, each R^(h) is independentlyselected from:

-   -   (1) halogen,    -   (2) C₁₋₄ alkyl,    -   (3) hydroxy,    -   (4) —O—C₁₋₁₄alkyl,    -   (5) —S—C₁₋₄alkyl,    -   (6) —CN,    -   (7) —CF₃, and    -   (8) —OCF₃.

In one class, each R^(h) is independently selected from:

-   -   (1) halogen,    -   (2) methyl,    -   (3) methoxy,    -   (4) hydroxy,    -   (5) methylthio-,    -   (6) —CN,    -   (7) —CF₃, and    -   (8) —OCF₃.

In one subclass, each R^(h) is independently selected from:

-   -   (1) halogen,    -   (2) methyl,    -   (3) hydroxy,    -   (4) methoxy,    -   (5) —CN,    -   (6) —CF₃, and    -   (7) —OCF₃.

In still another subclass, each R^(h) is independently selected from:

-   -   (1) halogen,    -   (2) methyl,    -   (3) methoxy,    -   (4) —CN,    -   (5) —CF₃, and    -   (6) —OCF₃.

In one embodiment of the present invention, m is two.

Still another embodiment of the present invention comprises compounds ofstructural formula IA:

Particular novel compounds which may be employed in the methods, usesand compositions of the present invention, include:

-   [3-amino-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)furo[2,3-b]pyridin-2-yl](phenyl)methanone,-   N-[2-benzoyl-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)furo[2,3-b]pyridin-3-yl]acetamide,-   N-[5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)-2-(2,2-dimethylpropanoyl)furo[2,3-b]pyridin-3-yl]butanamide,    N-[5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)-2-(2,2-dimethylpropanoyl)furo[2,3-b]pyridin-3-yl]pentanamide,-   1-[3-amino-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)furo[2,3-b]pyridin-2-yl]ethanone,-   N-[2-acetyl-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)furo[2,3-b]pyridin-3-yl]acetamide,-   N-[2-acetyl-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)furo[2,3-b]pyridin-3-yl]-N-(methylsulfonyl)methanesulfonamide,-   ethyl    3-amino-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)furo[2,3-b]pyridine-2-carboxylate,-   ethyl    3-(acetylamino)-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)furo[2,3-b]pyridine-2-carboxylate,    ethyl    5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)-3-[(trifluoroacetyl)amino]furo[2,3-b]pyridine-2-carboxylate,-   N-[5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)-2-(piperidin-1-ylcarbonyl)furo[2,3-b]pyridin-3-yl]acetamide,-   N-[5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)-2-(piperidin-1-ylcarbonyl)furo[2,3-b]pyridin-3-yl]-2,2,2-trifluoroacetamide,-   5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)-2-(piperidin-1-ylcarbonyl)furo[2,3-b]pyridin-3-amine,-   N-{5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)-2-[(4-methylpiperazin-1-yl)carbonyl]-furo[2,3-b]pyridin-3-yl}acetamide,    3-(acetylamino)-5-(4-chlorophenyl)-N-cyclopropyl-6-(2,4-dichlorophenyl)furo[2,3-b]pyridine-2-carboxamide,-   N-[5-(4-chlorophenyl)-6-(2,4    chlorophenyl)-2-(pyrrolidin-1-ylcarbonyl)furo[2,3-b]pyridin-3-yl]acetamide,    1-[3-amino-5-(4-chlorophenyl)-6-(2,4-chlorophenyl)furo[2,3-b]pyridin-2-yl]-2,2-dimethylpropan-1-one,-   N-[5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)-2-(2,2-dimethylpropanoyl)furo[2,3-b]pyridin-3-yl]acetamide,-   N-[5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)-2-(2,2-dimethylpropanoyl)furo[2,3-b]pyridin-3-yl]-2,2,2-trifluoroacetamide,-   N-[5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)-2-(2,2-dimethylpropanoyl)furo[2,3-b]pyridin-3-yl]-2-methoxyacetamide,-   N-[5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)-2-(2,2-dimethylpropanoyl)furo[2,3-b]pyridin-3-yl]-N,N-dimethylurea,-   N-[5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)-2-(2,2-dimethylpropanoyl)furo[2,3-b]pyridin-3-yl]morpholine-4-carboxamide,-   N-[5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)-2-(2,2-dimethylpropanoyl)furo[2,3-b]pyridin-3-yl]-N′-ethylurea,-   2-{[5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)-2-(2,2-dimethylpropanoyl)furo[2,3-b]pyridin-3-yl]amino}-2-oxoethyl    acetate,-   N-[5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)-2-(2,2-dimethylpropanoyl)furo[2,3-b]pyridin-3-yl]-2-hydroxyacetamide,-   [3-amino-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)furo[2,3-b]pyridin-2-yl](pyridin-3-yl)methanone,-   N-[5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)-2-(pyridin-3-ylcarbonyl)furo[2,3-b]pyridin-3-yl]-2,2-dimethylpropanamide,-   methyl    5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)-2-(pyridin-3-ylcarbonyl)furo[2,3-b]pyridin-3-ylcarbamate,-   N′-[5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)-2-(pyridin-3-ylcarbonyl)furo[2,3-b]pyridin-3-yl]-N,N-dimethylurea,-   N-[5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)-2-(pyridin-3-ylcarbonyl)furo[2,3-b]pyridin-3-yl]-2,2,2-trifluoroacetamide,-   [3-amino-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)furo[2,3-b]pyridin-2-yl](3,4-difluorophenyl)methanone,-   [3-amino-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)furo[2,3-b]pyridin-2-yl](3,4-difluorophenyl)methanone,-   N-[5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)-2-(2,2-dimethylpropanoyl)furo[2,3-b]pyridin-3-yl]sulfamide,-   N-[5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)-2-(2,2-dimethylpropanoyl)furo[2,3-b]pyridin-3-yl]methanesulfonamide,-   N-[2-(2-azabicyclo[2.2.2]oct-2-ylcarbonyl)-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)furo[2,3-b]pyridin-3-yl]acetamide,-   1-[3-amino-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)furo[2,3-b]pyridin-2-yl]propan-1-one,-   1-[5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)-3-(methylamino)furo[2,3-b]pyridin-2-yl]-2,2-dimethylpropan-1-one,-   1-[5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)-3-(dimethylamino)furo[2,3-b]pyridin-2-yl]-2,2-dimethylpropan-1-one,-   [5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)-3-(dimethylamino)furo[2,3-b]pyridin-2-yl](pyridin-3-yl)methanone,-   1-[5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)-3-(ethylamino)furo[2,3-b]pyridin-2-yl]-2,2-dimethylpropan-1-one,-   3-amino-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)furo[2,3-b]pyridine-2-carbonitrile,-   1-[3-amino-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)furo[2,3-b]pyridin-2-yl]-2-methylpropan-1-one,-   [3-amino-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)furo[2,3-b]pyridin-2-yl](cyclopropyl)methanone,-   [3-amino-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)furo[2,3-b]pyridin-2-yl](cyclobutyl)methanone,-   N-[5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)-2-isobutyrylfuro[2,3-b]pyridin-3-yl]-2-hydroxyacetamide,    N-[5-(4-chlorophenyl)-2-(cyclobutylcarbonyl)-6-(2,4-dichlorophenyl)furo[2,3-b]pyridin-3-yl]-2-hydroxyacetamide,    4-chloro-N-[5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)-2-(2,2-dimethylpropanoyl)furo[2,3-b]pyridin-3-yl]butanamide,-   1-[5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)-2-(2,2-dimethylpropanoyl)furo[2,3-b]pyridin-3-yl]pyrrolidin-2-one,-   N-[5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)-2-(2-hydroxy-2-methylpropanoyl)furo[2,3-b]pyridin-3-yl]-2-hydroxyacetamide,-   5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)-2-(3,4-difluorophenyl)furo[2,3-b]pyridin-3-ol    difluorophenyl)furo[2,3-b]pyridin-3-ol,-   1-[3-amino-6-(2-chlorophenyl)-5-(4-chlorophenyl)furo[2,3-b]pyridin-2-yl]-2,2-dimethylpropan-1-one,-   -[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2,2-dimethylpropanoyl)furo[2,3-b]pyridin-3-yl]acetamide,-   N-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2,2-dimethylpropanoyl)furo[2,3-b]pyridin-3-yl]-2-methoxyacetamide,-   2-{[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2,2-dimethylpropanoyl)furo[2,3-b]pyridin-3-yl]amino}-2-oxoethyl    acetate,-   NV-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2,2-dimethylpropanoyl)furo[2,3-b]pyridin-3-yl]-N,N-dimethylurea,-   N-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2,2-dimethylpropanoyl)furo[2,3-b]pyridin-3-yl]methanesulfonamide,-   N-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2,2-dimethylpropanoyl)furo[2,3-b]pyridin-3-yl]morpholine-4-carboxamide,-   2-chloro-N-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2,2-dimethylpropanoyl)furo[2,3-b]pyridin-3-yl]acetamide,-   (1S)-2-{[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2,2-dimethylpropanoyl)furo[2,3-b]pyridin-3-yl]amino}-1-methyl-2-oxoethyl    acetate,-   ethyl    [6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2,2-dimethylpropanoyl)furo[2,3-b]pyridin-3-yl]carbamate,-   ethyl    {[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2,2-dimethylpropanoyl)furo[2,3-b]pyridin-3-yl]amino}(oxo)acetate,-   N-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2,2-dimethyl-propanoyl)furo[2,3-b]pyridin-3-yl]-1-(trifluoroacetyl)-(S)-prolinamide,-   3-chloro-N-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2,2-dimethylpropanoyl)furo[2,3-b]pyridin-3-yl]propane-1-sulfonamide,-   1-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-3-(dimethylamino)furo[2,3-b]pyridin-2-yl]-2,2-dimethylpropan-1-one,-   1-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-3-(ethylamino)furo[2,3-b]pyridin-2-yl]-2,2-dimethylpropan-1-one,-   N′-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2,2-dimethylpropanoyl)furo[2,3-b]pyridin-3-yl]-N,N-dimethylimidoformamide,-   N-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2,2-dimethylpropanoyl)furo[2,3-b]pyridin-3-yl]acetamide,-   tert-butyl    [6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2,2-dimethylpropanoyl)furo[2,3-b]pyridin-3-yl]carbamate,-   1-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2,2-dimethylpropanoyl)furo[2,3-b]pyridin-3-yl]pyrrolidine-2,5-dione,-   4-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2,2-dimethylpropanoyl)furo[2,3-b]pyridin-3-yl]morpholine-3,5-dione,-   3-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2,2-dimethylpropanoyl)furo[2,3-b]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-2,4-dione,-   (3S)-1-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2,2-dimethylpropanoyl)furo[2,3-b]pyridin-3-yl]-3-hydroxypyrrolidine-2,5-dione,-   N-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2,2-dimethylpropanoyl)furo[2,3-b]pyridin-3-yl]-N-methylacetamide,-   N-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2,2-dimethylpropanoyl)furo[2,3-b]pyridin-3-yl]-2-hydroxyacetamide,-   N¹-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2,2-dimethylpropanoyl)furo[2,3-b]pyridin-3-yl]glycinamide,-   N¹-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2,2-dimethylpropanoyl)furo[2,3-b]pyridin-3-yl]-N²-methylglycinamide,-   N¹-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2,2-dimethylpropanoyl)furo[2,3-b]pyridin-3-yl]-N²,N²-dimethylglycinamide,-   (2S)-N-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2,2-dimethylpropanoyl)furo[2,3-b]pyridin-3-yl]-2-hydroxypropanamide,-   ethyl    allyl[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2,2-dimethylpropanoyl)furo[2,3-b]pyridin-3-yl]carbamate,-   ethyl    [6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2,2-dimethylpropanoyl)furo[2,3-b]pyridin-3-yl][2-(dimethylamino)ethyl]carbamate,-   1-[3-(allylamino)-6-(2-chlorophenyl)-5-(4-chlorophenyl)furo[2,3-b]pyridin-2-yl]-2,2-dimethylpropan-1-one,-   1-(6-(2-chlorophenyl)-5-(4-chlorophenyl)-3-{[2-(dimethylamino)ethyl]amino}furo[2,3-b]pyridin-2-yl)-2,2-dimethylpropan-1-one,-   N-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2,2-dimethylpropanoyl)furo[2,3-b]pyridin-3-yl]-L-prolinamide,-   1-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-3-(1,1-dioxidoisothiazolidin-2-yl)furo[2,3-b]pyridin-2-yl]-2,2-dimethylpropan-1-one,-   1-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2,2-dimethylpropanoyl)furo[2,3-b]pyridin-3-yl]-3-methylimidazolidin-2-one,-   1-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2-hydroxy-2-methylpropanoyl)furo[2,3-b]pyridin-3-yl]-3-methylimidazolidine-2,4-dione,-   1-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2,2-dimethylpropanoyl)furo[2,3-b]pyridin-3-yl]-4-methylpiperazine-2,3-dione,-   1-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2,2-dimethylpropanoyl)furo[2,3-b]pyridin-3-yl]-4-methylpiperazine-2,5-dione,-   1-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-3-hydroxyfuro[2,3-b]pyridin-2-yl]-2,2-dimethylpropan-1-one,-   1-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-3-methylfuro[2,3-b]pyridin-2-yl]-2,2-dimethylpropan-1-one,-   6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2,2-dimethylpropanoyl)furo[2,3-b]pyridine-3-carbaldehyde,-   methyl    6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2,2-dimethylpropanoyl)furo[2,3-b]pyridine-3-carboxylate,-   6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2,2-dimethylpropanoyl)-N,N-diethylfuro[2,3-b]pyridine-3-carboxamide,-   1-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-3-(4H-1,2,4-triazol-4-yl)furo[2,3-b]pyridin-2-yl]-2,2-dimethylpropan-1-one,-   1-[6-(2-chlorophenyl)-5-(4-chlorophenyl)furo[2,3-b]pyridin-2-yl]-2,2-dimethylpropan-1-one,-   1-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-3-(pyridin-2-ylamino)furo[2,3-b]pyridin-2-yl]-2,2-dimethylpropan-1-one,-   1-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-3-(pyrimidin-2-ylamino)-furo[2,3-b]pyridin-2-yl]-2,2-dimethylpropan-1-one,-   1-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-3-(pyridin-5-ylamino)-furo[2,3-b]pyridin-2-yl]-2,2-dimethylpropan-1-one,-   1-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-3-(pyridin-3-ylamino)-furo[2,3-b]pyridin-2-yl]-2,2-dimethylpropan-1-one,-   1-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-3-(pyridin-4-ylamino)-furo[2,3-b]pyridin-2-yl]-2,2-dimethylpropan-1-one,-   1-[3-amino-6-(2-chlorophenyl)-5-(4-chlorophenyl)furo[2,3-b]pyridin-2-yl]-2-hydroxy-2-methylpropan-1-one,-   N-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2-hydroxy-2-methylpropanoyl)furo[2,3-b]pyridin-3-yl]-2-hydroxyacetamide,-   N-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2-hydroxy-2-methylpropanoyl)furo[2,3-b]pyridin-3-yl]acetamide,-   N-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2-hydroxy-2-methylpropanoyl)furo[2,3-b]pyridin-3-yl]cyclopropanecarboxamide,-   N-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2-hydroxy-2-methylpropanoyl)furo[2,3-b]pyridin-3-yl]-2-methylpropanamide,-   N-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2-hydroxy-2-methylpropanoyl)furo[2,3-b]pyridin-3-yl]-3-methylbutanamide,-   N-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2-hydroxy-2-methylpropanoyl)furo[2,3-b]pyridin-3-yl]butanamide,-   N-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2-hydroxy-2-methylpropanoyl)furo[2,3-b]pyridin-3-yl]propanamide,-   N-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2-hydroxy-2-methylpropanoyl)furo[2,3-b]pyridin-3-yl]-2-methoxyacetamide,-   N-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2-hydroxy-2-methylpropanoyl)furo[2,3-b]pyridin-3-yl]-2-hydroxy-2-methylpropanamide,-   4-chloro-N-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2-hydroxy-2-methylpropanoyl)furo[2,3-b]pyridin-3-yl]butanamide,-   1-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2-hydroxy-2-methylpropanoyl)furo[2,3-b]pyridin-3-yl]pyrrolidin-2-one,-   N-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2-hydroxy-2-methylpropanoyl)furo[2,3-b]pyridin-3-yl]sulfamide,-   2-chloro-N-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2-hydroxy-2-methylpropanoyl)furo[2,3-b]pyridin-3-yl]acetamide,-   N¹-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2-hydroxy-2-methylpropanoyl)furo[2,3-b]pyridin-3-yl]-N²-methylglycinamide,-   N²-acetyl-N¹-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2-hydroxy-2-methylpropanoyl)furo[2,3-b]pyridin-3-yl]-N²-methylglycinamide,-   2-azetidin-1-yl-N-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2-hydroxy-2-methylpropanoyl)furo[2,3-b]pyridin-3-yl]acetamide,-   N-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2-hydroxy-2-methylpropanoyl)furo[2,3-b]pyridin-3-yl]-2-(1H-imidazol-1-yl)acetamide,-   1-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2-hydroxy-2-methylpropanoyl)furo[2,3-b]pyridin-3-yl]pyrrolidine-2,5-dione,-   methyl    3-{[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2-hydroxy-2-methylpropanoyl)furo[2,3-b]pyridin-3-yl]amino}-3-oxopropanoate,-   N²-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2-hydroxy-2-methylpropanoyl)furo[2,3-b]pyridin-3-yl]-N¹,N¹-dimethylglycinamide,-   ethyl    [6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2-hydroxy-2-methylpropanoyl)furo[2,3-b]pyridin-3-yl]carbamate,    N′-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2-hydroxy-2-methylpropanoyl)furo[2,3-b]pyridin-3-yl]-N,N-dimethylethanediamide,    N-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2-hydroxy-2-methylpropanoyl)furo[2,3-b]pyridin-3-yl]-N′-methylethanediamide,    N-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2-hydroxy-2-methylpropanoyl)furo[2,3-b]pyridin-3-yl]-N′-(2-hydroxyethyl)ethanediamide,-   N-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2-hydroxy-2-methylpropanoyl)furo[2,3-b]pyridin-3-yl]-N′-ethylethanediamide,-   N-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2-hydroxy-2-methylpropanoyl)furo[2,3-b]pyridin-3-yl]-2-oxo-2-pyrrolidin-1-ylacetamide,-   N-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2-hydroxy-2-methylpropanoyl)furo[2,3-b]pyridin-3-yl]-N′-ethylurea,-   N-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2-hydroxy-2-methylpropanoyl)furo[2,3-b]pyridin-3-yl]morpholine-4-carboxamide,-   N-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2-hydroxy-2-methylpropanoyl)furo[2,3-b]pyridin-3-yl]pyrrolidine-1-carboxamide,-   1-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-3-(methylamino)furo[2,3-b]pyridin-2-yl]-2-hydroxy-2-methylpropan-1-one,-   1-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2-hydroxy-2-methylpropanoyl)furo[2,3-b]pyridin-3-yl]imidazolidine-2,4-dione,-   1-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2-hydroxy-2-methylpropanoyl)furo[2,3-b]pyridin-3-yl]-3-methylimidazolidin-2-one,-   1-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2-hydroxy-2-methylpropanoyl)furo[2,3-b]pyridin-3-yl]-3-methylimidazolidine-2,4-dione,-   3-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2-hydroxy-2-methylpropanoyl)furo[2,3-b]pyridin-3-yl]-1,3-oxazolidin-2-one,-   N-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2-hydroxy-2-methylpropanoyl)furo[2,3-b]pyridin-3-yl]-N′,2,2-trimethylmalonamide,-   N-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2-hydroxy-2-methylpropanoyl)furo[2,3-b]pyridin-3-yl]-(S)-prolinamide,-   1-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-3-(1,1-dioxidoisothiazolidin-2-yl)furo[2,3-b]pyridin-2-yl]-2-hydroxy-2-methylpropan-1-one,-   N-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2-hydroxy-2-methylpropanoyl)furo[2,3-b]pyridin-3-yl]-2,2-dimethylmalonamide,-   1-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-3-methylfuro[2,3-b]pyridin-2-yl]-2-hydroxy-2-methylpropan-1-one,-   1-[3-amino-6-(2-chlorophenyl)-5-(4-chlorophenyl)furo[2,3-b]pyridin-2-yl]-2-methylpropan-1-one,-   2-{[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-isobutyrylfuro[2,3-b]pyridin-3-yl]amino}-2-oxoethyl    acetate,-   N-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-isobutyrylfuro[2,3-b]pyridin-3-yl]-2-hydroxyacetamide,-   N-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-isobutyrylfuro[2,3-b]pyridin-3-yl]-2-hydroxy-N-methylacetamide,-   N-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-isobutyrylfuro[2,3-b]pyridin-3-yl]acetamide,-   4-chloro-N-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-isobutyrylfuro[2,3-b]pyridin-3-yl]butanamide,-   1-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-isobutyrylfuro[2,3-b]pyridin-3-yl]pyrrolidin-2-one,-   N-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-isobutyrylfuro[2,3-b]pyridin-3-yl]-N-methylacetamide,-   1-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-isobutyrylfuro[2,3-b]pyridin-3-yl]pyrrolidine-2,5-dione,-   4-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-isobutyrylfuro[2,3-b]pyridin-3-yl]morpholine-3,5-dione,-   N-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-isobutyrylfuro[2,3-b]pyridin-3-yl]methanesulfonamide,-   1-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-isobutyrylfuro[2,3-b]pyridin-3-yl]imidazolidine-2,4-dione,-   N-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-isobutyrylfuro[2,3-b]pyridin-3-yl]urea,-   1-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-isobutyrylfuro[2,3-b]pyridin-3-yl]piperidine-2,6-dione,-   3-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-isobutyrylfuro[2,3-b]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-2,4-dione,-   1-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-3-(1,1-dioxidoisothiazolidin-2-yl)furo[2,3-b]pyridin-2-yl]-2-methylpropan-1-one,-   N-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-isobutyrylfuro[2,3-b]pyridin-3-yl]-N-methylmethanesulfonamide,-   [3-amino-6-(2-chlorophenyl)-5-(4-chlorophenyl)furo[2,3-b]pyridin-2-yl](pyridin-3-yl)methanone,    N-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(pyridin-3-ylcarbonyl)furo[2,3-b]pyridin-3-yl]-2-hydroxyacetamide,-   [3-amino-6-(2-chlorophenyl)-5-(4-chlorophenyl)furo[2,3-b]pyridin-2-yl](2-furyl)-methanone,-   N-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2-furoyl)furo[2,3-b]pyridin-3-yl]acetamide,    N-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2-furoyl)furo[2,3-b]pyridin-3-yl]acetamide,-   2-(tert-butylsulfonyl)-6-(2-chlorophenyl)-5-(4-chlorophenyl)furo[2,3-b]pyridin-3-amine,-   N-[2-(tert-butylsulfonyl)-6-(2-chlorophenyl)-5-(4-chlorophenyl)-furo[2,3-b]pyridin-3-yl]methanesulfonamide,-   N-[2-(tert-butylsulfonyl)-6-(2-chlorophenyl)-5-(4-chlorophenyl)-furo[2,3-b]pyridin-3-yl]acetimide,-   N-[2-(tert-butylsulfonyl)-6-(2-chlorophenyl)-5-(4-chlorophenyl)-furo[2,3-b]pyridin-3-yl]acetamide,-   2-{[2-(tert-butylsulfonyl)-6-(2-chlorophenyl)-5-(4-chlorophenyl)-furo[2,3-b]pyridin-3-yl]amino}I-2-oxoethyl    acetate,-   N-[2-(tert-butylsulfonyl)-6-(2-chlorophenyl)-5-(4-chlorophenyl)-furo[2,3-b]pyridin-3-yl]-2-hydroxyacetamide,-   1-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(methylsulfonyl)-furo[2,3-b]pyridin-3-yl]pyrrolidine-2,5-dione,-   N-[2-(tert-butylsulfonyl)-6-(2-chlorophenyl)-5-(4-chlorophenyl)-furo[2,3-b]pyridin-3-yl]-N-methylmethanesulfonamide,-   N-[2-(tert-butylsulfonyl)-6-(2-chlorophenyl)-5-(4-chlorophenyl)-furo[2,3-b]pyridin-3-yl]-N-methylacetamide,-   1-[2-(tert-butylsulfonyl)-6-(2-chlorophenyl)-5-(4-chlorophenyl)-furo[2,3-b]pyridin-3-yl]imidazolidine-2,4-dione,    6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(phenylsulfonyl)furo[2,3-b]pyridin-3-amine,-   2-{[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(phenylsulfonyl)furo[2,3-b]pyridin-3-yl]amino}-2-oxoethyl    acetate,-   N-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(phenylsulfonyl)furo[2,3-b]pyridin-3-yl]-2-hydroxyacetamide,-   2-chloro-N-({[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(phenylsulfonyl)furo[2,3-b]pyridin-3-yl]amino}-carbonyl)acetamide,-   1-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(phenylsulfonyl)furo[2,3-b]pyridin-3-yl]imidazolidine-2,4-dione,-   6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(methylsulfonyl)furo[2,3-b]pyridin-3-amine,    N-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(methylsulfonyl)-furo[2,3-b]pyridine-3-yl]acetamide,-   N-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(methylsulfonyl)-furo[2,3-b]pyridin-3-yl]butanamide,-   ethyl    3-amino-6-(2-chlorophenyl)-5-(4-chlorophenyl)furo[2,3-b]pyridine-2-carboxylate    2-carboxylate,-   ethyl    6-(2-chlorophenyl)-5-(4-chlorophenyl)-3-[(trifluoroacetyl)amino]furo[2,3-b]pyridine-2-carboxylate,-   6-(2-chlorophenyl)-5-(4-chlorophenyl)-N,N-diethyl-3-[(trifluoroacetyl)amino]furo[2,3-b]pyridine-2-carboxamide,-   3-amino-6-(2-chlorophenyl)-5-(4-chlorophenyl)-N,N-diethylfuro[2,3-b]pyridine-2-carboxamide,-   3-(acetylamino)-6-(2-chlorophenyl)-5-(4-chlorophenyl)-N,N-diethylo[2,3-b]pyridine-2-carboxamide,-   3-(acetylamino)-6-(2-chlorophenyl)-5-(4-chlorophenyl)-N-ethyl-N-methylfuro[2,3-b]pyridine-2-carboxamide,-   6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(piperidin-1-ylcarbonyl)furo[2,3-b]pyridin-3-amine,-   N-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(piperidin-1-ylcarbonyl)furo[2,3-b]pyridin-3-yl]acetamide,-   6-(2-chlorophenyl)-5-(4-chlorophenyl)-N,N-diethyl-3-(glycoloylamino)furo[2,3-b]pyridine-2-carboxamide,-   6-(2-chlorophenyl)-5-(4-chlorophenyl)-3-(glycoloylamino)-N,N-dimethylfuro[2,3-b]pyridine-2-carboxamide,-   6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(pyrrolidin-1-ylcarbonyl)furo[2,3-b]pyridin-3-amine,-   1-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(pyrrolidin-1-ylcarbonyl)furo[2,3-b]pyridin-3-yl]pyrrolidine-2,5-dione,-   1-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(pyrrolidin-1-ylcarbonyl)furo[2,3-b]pyridin-3-yl]-3-methylimidazolidine-2,4-dione,-   6-(2-chlorophenyl)-5-(4-chlorophenyl)-3-(2,4-dioxoimidazolidin-1-yl)-N,N-diethylfuro[2,3-b]pyridine-2-carboxamide,-   6-(2-chlorophenyl)-5-(4-chlorophenyl)-N,N-diethyl-3-[(methylsulfonyl)amino]furo[2,3-b]pyridine-2-carboxamide,-   6-(2-chlorophenyl)-5-(4-chlorophenyl)-N,N-diethyl-3-[(propylsulfonyl)amino]furo[2,3-b]pyridine-2-carboxamide,-   6-(2-chlorophenyl)-5-(4-chlorophenyl)-3-(2,5-dioxopyrrolidin-1-yl)-N,N-diethylfuro[2,3-b]pyridine-2-carboxamide,-   1-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-3-(1-methyl-1H-imidazol-2-yl)furo[2,3-b]pyridin-2-yl]-2,2-dimethylpropan-1-one,-   4-[3-amino-5-(4-chlorophenyl)-2-(2-hydroxy-2-methylpropanoyl)furo[2,3-b]pyridin-6-yl]-3-chlorobenzonitrile,-   N-[6-(2-chloro-4-cyanophenyl)-5-(4-chlorophenyl)-2-(2-hydroxy-2-methylpropanoyl)furo[2,3-b]pyridin-3-yl]acetamide,-   3-[3-amino-6-(2,4-dichlorophenyl)-2-(2,2-dimethylpropanoyl)furo[2,3-b]pyridin-5-yl]benzonitrile,-   4-[3-amino-6-(2-chlorophenyl)-2-(2-hydroxy-2-methylpropanoyl)furo[2,3-b]pyridin-5-yl]benzonitrile,-   N-[6-(2-chlorophenyl)-5-(4-cyanophenyl)-2-(2-hydroxy-2-methylpropanoyl)furo[2,3-b]pyridin-3-yl]acetamide,-   1-[3-amino-6-(1,3-benzodioxol-5-yl)-5-(4-chlorophenyl)furo[2,3-b]pyridin-2-yl]-2,2-dimethylpropan-1-one,    1-[3-amino-6-(2-chloro-4-fluorophenyl)-5-(4-chlorophenyl)furo[2,3-b]pyridin-2-yl]-2,2-dimethylpropan-1-one,-   N-[6-(2-chloro-4-fluorophenyl)-5-(4-chlorophenyl)-2-(2,2-dimethylpropanoyl)furo[2,3-b]pyridin-3-yl]-2-methoxyacetamide,-   N-[6-(2-chloro-4-fluorophenyl)-5-(4-chlorophenyl)-2-(2-hydroxy-2-methylpropanoyl)furo[2,3-b]pyridin-3-yl]-2-hydroxyacetamide,-   N-[5-(4-chlorophenyl)-6-(2-cyanophenyl)-2-(2-hydroxy-2-methylpropanoyl)furo[2,3-b]pyridin-3-yl]acetamide,-   N-[5-(4-chlorophenyl)-6-(2-cyanophenyl)-2-(2,2-dimethylpropanoyl)furo[2,3-b]pyridin-3-yl]acetamide,-   N-[5-(4-chlorophenyl)-6-(2-cyanophenyl)-2-(2,2-dimethylpropanoyl)furo[2,3-b]pyridin-3-yl]-2-hydroxyacetamide,-   N-[6-(4-chloro-2-cyanophenyl)-5-(4-chlorophenyl)-2-(2-hydroxy-2-methylpropanoyl)furo[2,3-b]pyridin-3-yl]acetamide,-   N-[6-(2-chlorophenyl)-2-(2-hydroxy-2-methylpropanoyl)-5-(4-methoxyphenyl)furo[2,3-b]pyridin-3-yl]acetamide,    N-[6-(2-chlorophenyl)-2-(2,2-dimethylpropanoyl)-5-(4-methoxyphenyl)furo[2,3-b]pyridin-3-yl]acetamide,    and pharmaceutically acceptable salts thereof.

“Alkyl”, as well as other groups having the prefix “alk”, such asalkoxy, alkanoyl, means carbon chains which may be linear or branched orcombinations thereof. Examples of alkyl groups include methyl, ethyl,propyl, isopropyl, butyl, sec- and tert-butyl, pentyl, hexyl, heptyl,octyl, nonyl, and the like.

“Alkenyl” means carbon chains which contain at least one carbon-carbondouble bond, and which may be linear or branched or combinationsthereof. Examples of alkenyl include vinyl, allyl, isopropenyl,pentenyl, hexenyl, heptenyl, 1-propenyl, 2-butenyl, 2-methyl-2-butenyl,and the like.

“Alkynyl” means carbon chains which contain at least one carbon-carbontriple bond, and which may be linear or branched or combinationsthereof. Examples of alkynyl include ethynyl, propargyl,3-methyl-1-pentynyl, 2-heptynyl and the like.

“Cycloalkyl” means mono- or bicyclic or bridged saturated carbocyclicrings, each having from 3 to 10 carbon atoms. The term also includesmonocyclic rings fused to an aryl group in which the point of attachmentis on the non-aromatic portion. Examples of cycloalkyl includecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,tetrahydronaphthyl, decahydronaphthyl, indanyl, and the like.

“Aryl” means mono- or bicyclic aromatic rings containing only carbonatoms. The term also includes aryl group fused to a monocycliccycloalkyl or monocyclic cycloheteroalkyl group in which the point ofattachment is on the aromatic portion. Examples of aryl include phenyl,naphthyl, indanyl, indenyl, tetrahydronaphthyl, 2,3-dihydrobenzofuranyl,dihydrobenzopyranyl, 1,4-benzodioxanyl, 1,3-benzodioxol-5-yl, and thelike. A preferred aryl substituent is phenyl.

“Heteroaryl” means a mono- or bicyclic aromatic ring containing at leastone heteroatom selected from N, O and S, with each ring containing 5 to6 atoms. Examples of heteroaryl include pyrrolyl, isoxazolyl,isothiazolyl, pyrazolyl, pyridyl, oxazolyl, oxadiazolyl, thiadiazolyl,thiazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, triazinyl,thienyl, pyrimidyl, pyridazinyl, pyrazinyl, benzoxazolyl,benzothiazolyl, benzimidazolyl, benzofuranyl, benzothiophenyl,benzothiazolyl, furo(2,3-b)pyridyl, quinolyl, indolyl, isoquinolyl,oxazolidinyl, and the like. The heteroaryl ring may be substituted onone or more carbon atoms. In one embodiment of the present invention,heteroaryl is pyridinyl, pyrazinyl, benzimidazolyl, imidazolyl, andfuranyl. In one class of this embodiment, heteroaryl is pyridinyl,pyrazinyl, and furanyl. “Cycloheteroalkyl” means mono- or bicyclic orbridged saturated rings containing at least one heteroatom selected fromN, S and O, each of said ring having from 3 to 10 atoms in which thepoint of attachment may be carbon or nitrogen. The term also refers tobridged rings, and also includes monocyclic heterocycle fused to an arylor heteroaryl group in which the point of attachment is on thenon-aromatic portion The term also includes partially unsaturatedmonocyclic rings that are not aromatic, such as 2- or 4-pyridonesattached through the nitrogen or N-substituted-(1H,3H)-pyrimidine-2,4-diones (N-substituted uracils). The cycloheteroalkylring may be substituted on the ring carbons and/or the ring nitrogensExamples of “cycloheteroalkyl” include: azetidinyl, pyrrolidinyl,piperidinyl, piperazinyl, imidazolidinyl, morpholinyl,dihydroisoindolyl, pyranyl, perhydroazepinyl, tetrahydrofuranyl,dioxanyl, oxanyl, 1-thia-4-aza-cyclohexane (thiomorpholinyl),2,5-diazabicyclo[2.2.2]octanyl, benzoxazinyl, tetrahydroquinolinyl,tetrahydroisoquinolinyl, dihydroindolyl, dihydroisoindolyl, indolyl,indolinyl, isoindolinyl, isothiazolindinyl, 1,3-dihydro-2-benzofuranyl,benzodioxolyl, hexahydrothienopyridinyl, thienopyridinyl,azacycloheptyl, azabicyclo[3.1.0]hexyl, 2-oxa-5-azabicyclo[2.2.1]heptyl,2,5-diazabicyclo[2.2.1]heptyl, 2-azabicyclo[2.2.1]heptyl,7-azabicyclo[2.2.1.]heptyl, 2,4-dizaobicyclo[2.2.2]octyl,2-azabicyclo[2.2.2]octyl, 3-azabicyclo[3.2.2]nonyl, 2H-pyrrolyl,4,4-spiro[2,3-dihydrobenzothiophen-3,3-yl]piperidinyl,4,4-spiro[indoli-3,3-yl]piperidinyl, and the like. In one embodiment ofthe present invention, cycloheteroalkyl is: azetindinyl, pyrrolidinyl,piperidinyl, piperazinyl, imidazolidinyl, morpholinyl,1-thia-4-aza-cyclohexane (thiomorpholinyl), isothiazolidinyl,andazabicyclo[3.1.0]hexyl,

“Halogen” includes fluorine, chlorine, bromine and iodine.

When any variable (e.g., R¹, R^(d), etc.) occurs more than one time inany constituent or in formula I, its definition on each occurrence isindependent of its definition at every other occurrence. Also,combinations of substituents and/or variables are permissible only ifsuch combinations result in stable compounds.

Under standard nomenclature used throughout this disclosure, theterminal portion of the designated side chain is described first,followed by the adjacent functionality toward the point of attachment.For example, a C₁₋₅ alkylcarbonylamino C₁₋₆ alkyl substituent isequivalent to

In choosing compounds of the present invention, one of ordinary skill inthe art will recognize that the various substituents, i.e. R¹, R², etc.,are to be chosen in conformity with well-known principles of chemicalstructure connectivity and stability.

The term “substituted” shall be deemed to include multiple degrees ofsubstitution by a named substitutent. Where multiple substituentmoieties are disclosed or claimed, the substituted compound can beindependently substituted by one or more of the disclosed or claimedsubstituent moieties, singly or plurally. By independently substituted,it is meant that the (two or more) substituents can be the same ordifferent.

Compounds of Formula I may contain one or more asymmetric centers andcan thus occur as racemates and racemic mixtures, single enantiomers,diastereomeric mixtures and individual diastereomers. The presentinvention is meant to comprehend all such isomeric forms of thecompounds of Formula I.

Some of the compounds described herein contain olefinic double bonds,and unless specified otherwise, are meant to include both E and Zgeometric isomers.

Tautomers are defined as compounds that undergo rapid proton shifts fromone atom of the compound to another atom of the compound. Some of thecompounds described herein may exist as tautomers with different pointsof attachment of hydrogen. Such an example may be a ketone and its enolform known as keto-enol tautomers. The individual tautomers as well asmixture thereof are encompassed with compounds of Formula I.

Compounds of the Formula I may be separated into diastereoisomeric pairsof enantiomers by, for example, fractional crystallization from asuitable solvent, for example MeOH or ethyl acetate or a mixturethereof. The pair of enantiomers thus obtained may be separated intoindividual stereoisomers by conventional means, for example by the useof an optically active amine as a resolving agent or on a chiral HPLCcolumn.

Alternatively, any enantiomer of a compound of the general Formula I maybe obtained by stereospecific synthesis using optically pure startingmaterials or reagents of known configuration.

Furthermore, some of the crystalline forms for compounds of the presentinvention may exist as polymorphs and as such are intended to beincluded in the present invention. In addition, some of the compounds ofthe instant invention may form solvates with water or common organicsolvents. Such solvates are encompassed within the scope of thisinvention.

It is generally preferable to administer compounds of the presentinvention as enantiomerically pure formulations. Racemic mixtures can beseparated into their individual enantiomers by any of a number ofconventional methods. These include chiral chromatography,derivatization with a chiral auxiliary followed by separation bychromatography or crystallization, and fractional crystallization ofdiastereomeric salts.

The term “pharmaceutically acceptable salts” refers to salts preparedfrom pharmaceutically acceptable non-toxic bases or acids includinginorganic or organic bases and inorganic or organic acids. Salts derivedfrom inorganic bases include aluminum, ammonium, calcium, copper,ferric, ferrous, lithium, magnesium, manganic salts, manganous,potassium, sodium, zinc, and the like. Particularly preferred are theammonium, calcium, magnesium, potassium, and sodium salts. Salts derivedfrom pharmaceutically acceptable organic non-toxic bases include saltsof primary, secondary, and tertiary amines, substituted amines includingnaturally occurring substituted amines, cyclic amines, and basic ionexchange resins, such as arginine, betaine, caffeine, choline,N,N′-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol,2-dimethylaminoethanol, ethanolamine, ethylenediamine,N-ethyl-morpholine, N-ethylpiperidine, glucamine, glucosamine,histidine, hydrabamine, isopropylamine, lysine, methylglucamine,morpholine, piperazine, piperidine, polyamine resins, procaine, purines,theobromine, triethylamine, trimethylamine, tripropylamine,tromethamine, and the like. The term “pharmaceutically acceptable salt”further includes all acceptable salts such as acetate, lactobionate,benzenesulfonate, laurate, benzoate, malate, bicarbonate, maleate,bisulfate, mandelate, bitartrate, mesylate, borate, methylbromide,bromide, methylnitrate, calcium edetate, methylsulfate, camsylate,mucate, carbonate, napsylate, chloride, nitrate, clavulanate,N-methylglucamine, citrate, ammonium salt, dihydrochloride, oleate,edetate, oxalate, edisylate, pamoate (embonate), estolate, palmitate,esylate, pantothenate, fumarate, phosphate/diphosphate, gluceptate,polygalacturonate, gluconate, salicylate, glutamate, stearate,glycollylarsanilate, sulfate, hexylresorcinate, subacetate, hydrabamine,succinate, hydrobromide, tannate, hydrochloride, tartrate,hydroxynaphthoate, teoclate, iodide, tosylate, isothionate,triethiodide, lactate, panoate, valerate, and the like which can be usedas a dosage form for modifying the solubility or hydrolysischaracteristics or can be used in sustained release or pro-drugformulations.

It will be understood that, as used herein, references to the compoundsof Formula I are meant to also include the pharmaceutically acceptablesalts.

Compounds of the present invention are modulators of the CB1 receptor.In particular, the compounds of structural formula I are antagonists orinverse agonists of the CB1 receptor.

An “agonist” is a compound (hormone, neurotransmitter or syntheticcompound) which binds to a receptor and mimics the effects of theendogenous regulatory compound, such as contraction, relaxation,secretion, change in enzyme activity, etc. An “antagonist” is acompound, devoid of intrinsic regulatory activity, which produceseffects by interfering with the binding of the endogenous agonist orinhibiting the action of an agonist. An “inverse agonist” is a compoundwhich acts on a receptor but produces the opposite effect produced bythe agonist of the particular receptor.

Compounds of this invention are modulators of the CB1 receptor and assuch are useful as centrally acting drugs in the treatment of psychosis,memory deficits, cognitive disorders, migraine, neuropathy,neuro-inflammatory disorders including multiple sclerosis andGuillain-Barre syndrome and the inflammatory sequelae of viralencephalitis, cerebral vascular accidents, and head trauma, anxietydisorders, stress, epilepsy, Parkinson's disease, movement disorders,and schizophrenia. The compounds are also useful for the treatment ofsubstance abuse disorders, particularly to opiates, alcohol, marijuana,and nicotine. The compounds are also useful for the treatment of obesityor eating disorders associated with excessive food intake andcomplications associated therewith, including left ventricularhypertrophy. The compounds are also useful for the treatment ofconstipation and chronic intestinal pseudo-obstruction. The compoundsare also useful for the treatment of cirrhosis of the liver. Thecompounds are also useful for the treatment of asthma.

The terms “administration of” and or “administering a” compound shouldbe understood to mean providing a compound of the invention or a prodrugof a compound of the invention to the individual in need of treatment.

The administration of the compound of structural formula I in order topractice the present methods of therapy is carried out by administeringan effective amount of the compound of structural formula I to thepatient in need of such treatment or prophylaxis. The need for aprophylactic administration according to the methods of the presentinvention is determined via the use of well known risk factors. Theeffective amount of an individual compound is determined, in the finalanalysis, by the physician in charge of the case, but depends on factorssuch as the exact disease to be treated, the severity of the disease andother diseases or conditions from which the patient suffers, the chosenroute of administration other drugs and treatments which the patient mayconcomitantly require, and other factors in the physician's judgment.

The utilities of the present compounds in these diseases or disordersmay be demonstrated in animal disease models that have been reported inthe literature. The following are examples of such animal diseasemodels: a) suppression of food intake and resultant weight loss in rats(Life Sciences 1998, 63, 113-117); b) reduction of sweet food intake inmarmosets (Behavioural Pharm. 1998, 9, 179-181); c) reduction of sucroseand ethanol intake in mice (Psychopharm. 1997, 132, 104-106); d)increased motor activity and place conditioning in rats (Psychopharm.1998, 135, 324-332; Psychopharmacol 2000, 151: 25-30); e) spontaneouslocomotor activity in mice (J. Pharm. Exp. Ther. 1996, 277, 586-594); f)reduction in opiate self-administration in mice (Sci. 1999, 283,401-404); g) bronchial hyperresponsiveness in sheep and guinea pigs asmodels for the various phases of asthma (for example, see W. M. Abrahamet al., “α₄-Integrins mediate antigen-induced late bronchial responsesand prolonged airway hyperresponsiveness in sheep.” J. Clin. Invest. 93,776 (1993) and A. A. Y. Mine and P. P. Piper, “Role of VLA-4 integrin inleucocyte recruitment and bronchial hyperresponsiveness in theguinea-pig.” Eur. J. Pharmacol., 282, 243 (1995)); h) mediation of thevasodilated state in advanced liver cirrhosis induced by carbontetrachloride (Nature Medicine, 2001, 7 (7), 827-832); i)amitriptyline-induced constipation in cynomolgus monkeys is beneficialfor the evaluation of laxatives (Biol. Pharm. Bulletin (Japan), 2000,23(5), 657-9); j) neuropathology of paediatric chronic intestinalpseudo-obstruction and animal models related to the neuropathology ofpaediatric chronic intestinal pseudo-obstruction (Journal of Pathology(England), 2001, 194 (3), 277-88).

The magnitude of prophylactic or therapeutic dose of a compound ofFormula I will, of course, vary with the nature of the severity of thecondition to be treated and with the particular compound of Formula Iand its route of administration. It will also vary according to the age,weight and response of the individual patient. In general, the dailydose range lie within the range of from about 0.001 mg to about 100 mgper kg body weight of a mammal, preferably 0.01 mg to about 50 mg perkg, and most preferably 0.1 to 10 mg per kg, in single or divided doses.On the other hand, it may be necessary to use dosages outside theselimits in some cases.

For use where a composition for intravenous administration is employed,a suitable dosage range is from about 0.001 mg to about 100 mg in oneembodiment from 0.01 mg to about 50 mg, and in another embodiment from0.1 mg to 10 mg of a compound of Formula I per kg of body weight perday.

In the case where an oral composition is employed, a suitable dosagerange is, e.g. from about 0.01 mg to about 1000 mg of a compound ofFormula I per day, preferably from about 0.1 mg to about 10 mg per day.For oral administration, the compositions are preferably provided in theform of tablets containing from 0.01 to 1,000 mg, preferably 0.01, 0.05,0.1, 0.5, 1, 2.5, 5, 10, 15, 20, 25, 30, 40, 50, 100, 250, 500, 750 or1000 milligrams of the active ingredient for the symptomatic adjustmentof the dosage to the patient to be treated.

For the treatment of diseases of the eye, ophthalmic preparations forocular administration comprising 0.001-1% by weight solutions orsuspensions of the compounds of Formula I in an acceptable ophthalmicformulation may be used.

Another aspect of the present invention provides pharmaceuticalcompositions which comprises a compound of Formula I and apharmaceutically acceptable carrier. The term “composition”, as inpharmaceutical composition, is intended to encompass a productcomprising the active ingredient(s), and the inert ingredient(s)(pharmaceutically acceptable excipients) that make up the carrier, aswell as any product which results, directly or indirectly, fromcombination, complexation or aggregation of any two or more of theingredients, or from dissociation of one or more of the ingredients, orfrom other types of reactions or interactions of one or more of theingredients. Accordingly, the pharmaceutical compositions of the presentinvention encompass any composition made by admixing a compound ofFormula I, additional active ingredient(s), and pharmaceuticallyacceptable excipients.

Any suitable route of administration may be employed for providing amammal, specially a human, with an effective dosage of a compound of thepresent invention. For example, oral, rectal, topical, parenteral,ocular, pulmonary, nasal, and the like may be employed. Dosage formsinclude tablets, troches, dispersions, suspensions, solutions, capsules,creams, ointments, aerosols, and the like.

The pharmaceutical compositions of the present invention comprise acompound of Formula I as an active ingredient or a pharmaceuticallyacceptable salt thereof, and may also contain a pharmaceuticallyacceptable carrier and optionally other therapeutic ingredients. By“pharmaceutically acceptable” it is meant the carrier, diluent orexcipient must be compatible with the other ingredients of theformulation and not deleterious to the recipient thereof. In particular,the term “pharmaceutically acceptable salts” refers to salts preparedfrom pharmaceutically acceptable non-toxic bases or acids includinginorganic bases or acids and organic bases or acids.

The compositions include compositions suitable for oral, rectal,topical, parenteral (including subcutaneous, intramuscular, andintravenous), ocular (ophthalmic), pulmonary (aerosol inhalation), ornasal administration, although the most suitable route in any given casewill depend on the nature and severity of the conditions being treatedand on the nature of the active ingredient. They may be convenientlypresented in unit dosage form and prepared by any of the methodswell-known in the art of pharmacy.

For administration by inhalation, the compounds of the present inventionare conveniently delivered in the form of an aerosol spray presentationfrom pressurized packs or nebulizers. The compounds may also bedelivered as powders which may be formulated and the powder compositionmay be inhaled with the aid of an insufflation powder inhaler device.The preferred delivery systems for inhalation are metered doseinhalation (MDI) aerosol, which may be formulated as a suspension orsolution of a compound of Formula I in suitable propellants, such asfluorocarbons or hydrocarbons and dry powder inhalation (DPI) aerosol,which may be formulated as a dry powder of a compound of Formula I withor without additional excipients.

Suitable topical formulations of a compound of formula I includetransdermal devices, aerosols, crearms, solutions, ointments, gels,lotions, dusting powders, and the like. The topical pharmaceuticalcompositions containing the compounds of the present inventionordinarily include about 0.005% to 5% by weight of the active compoundin admixture with a pharmaceutically acceptable vehicle. Transdermalskin patches useful for administering the compounds of the presentinvention include those well known to those of ordinary skill in thatart. To be administered in the form of a transdermal delivery system,the dosage administration will, of course be continuous rather thanintermittent throughout the dosage regimen.

In practical use, the compounds of Formula I can be combined as theactive ingredient in intimate admixture with a pharmaceutical carrieraccording to conventional pharmaceutical compounding techniques. Thecarrier may take a wide variety of forms depending on the form ofpreparation desired for administration, e.g., oral or parenteral(including intravenous). In preparing the compositions for oral dosageform, any of the usual pharmaceutical media may be employed, such as,for example, water, glycols, oils, alcohols, flavoring agents,preservatives, coloring agents and the like in the case of oral liquidpreparations, such as, for example, suspensions, elixirs and solutions;or carriers such as starches, sugars, microcrystalline cellulose,diluents, granulating agents, lubricants, binders, disintegrating agentsand the like in the case of oral solid preparations such as, forexample, powders, capsules and tablets, with the solid oral preparationsbeing preferred over the liquid preparations. Because of their ease ofadministration, tablets and capsules represent the most advantageousoral dosage unit form in which case solid pharmaceutical carriers areobviously employed. If desired, tablets may be coated by standardaqueous or nonaqueous techniques.

In addition to the common dosage forms set out above, the compounds ofFormula I may also be administered by controlled release means and/ordelivery devices such as those described in U.S. Pat. Nos. 3,845,770;3,916,899; 3,536,809; 3,598,123; 3,630,200 and 4,008,719.

Pharmaceutical compositions of the present invention suitable for oraladministration may be presented as discrete units such as capsules(including timed release and sustained release formulations), pills,cachets, powders, granules or tablets each containing a predeterminedamount of the active ingredient, as a powder or granules or as asolution or a suspension in an aqueous liquid, a non-aqueous liquid, anoil-in-water emulsion or a water-in-oil liquid emulsion, includingelixirs, tinctures, solutions, suspensions, syrups and emulsions. Suchcompositions may be prepared by any of the methods of pharmacy but allmethods include the step of bringing into association the activeingredient with the carrier which constitutes one or more necessaryingredients. In general, the compositions are prepared by uniformly andintimately admixing the active ingredient with liquid carriers or finelydivided solid carriers or both, and then, if necessary, shaping theproduct into the desired presentation. For example, a tablet may beprepared by compression or molding, optionally with one or moreaccessory ingredients. Compressed tablets may be prepared by compressingin a suitable machine, the active ingredient in a free-flowing form suchas powder or granules, optionally mixed with a binder, lubricant, inertdiluent, surface active or dispersing agent. Molded tablets may be madeby molding in a suitable machine, a mixture of the powdered compoundmoistened with an inert liquid diluent. Desirably, each tablet containsfrom 0.01 to 1,000 mg, particularly 0.01, 0.05, 0.1, 0.5, 1, 2.5, 3, 5,6, 10, 15, 25, 50, 75, 100, 125, 150, 175, 180, 200, 225, 500, 750 and1,000 milligrams of the active ingredient for the symptomatic adjustmentof the dosage to the patient to be treated and each cachet or capsulecontains from about 0.01 to 1,000 mg, particularly 0.01, 0.05, 0.1, 0.5,1.0, 2.5, 3, 5, 6, 10, 15, 25, 50, 75, 100, 125, 150, 175, 180, 200,225, 500, 750 and 1,000 milligrams of the active ingredient for thesymptomatic adjustment of the dosage to the patient to be treated.

Additional suitable means of administration of the compounds of thepresent invention include injection, intravenous bolus or infusion,intraperitoneal, subcutaneous, intramuscular and topical, with orwithout occlusion.

Exemplifying the invention is a pharmaceutical composition comprisingany of the compounds described above and a pharmaceutically acceptablecarrier. Also exemplifying the invention is a pharmaceutical compositionmade by combining any of the compounds described above and apharmaceutically acceptable carrier. An illustration of the invention isa process for making a pharmaceutical composition comprising combiningany of the compounds described above and a pharmaceutically acceptablecarrier.

The dose may be administered in a single daily dose or the total dailydosage may be administered in divided doses of two, three or four timesdaily. Furthermore, based on the properties of the individual compoundselected for administration, the dose may be administered lessfrequently, e.g., weekly, twice weekly, monthly, etc. The unit dosagewill, of course, be correspondingly larger for the less frequentadministration.

When administered via intranasal routes, transdermal routes, by rectalor vaginal suppositories, or through a continual intravenous solution,the dosage administration will, of course, be continuous rather thanintermittent throughout the dosage regimen.

The following are examples of representative pharmaceutical dosage formsfor the compounds of Formula I: Injectable Suspension (I.M.) mg/mLCompound of Formula I 10 Methylcellulose 5.0 Tween 80 0.5 Benzyl alcohol9.0 Benzalkonium chloride 1.0 Water for injection to a total volume of 1mL Tablet mg/tablet Compound of Formula I 25 Microcrystalline Cellulose415 Povidone 14.0 Pregelatinized Starch 43.5 Magnesium Stearate 2.5 500Capsule mg/capsule Compound of Formula I 25 Lactose Powder 573.5Magnesium Stearate 1.5 600 Aerosol Per canister Compound of Formula I 24mg Lecithin, NF Liq. Conc. 1.2 mg Trichlorofluoromethane, NF 4.025 gDichlorodifluoromethane, NF 12.15 g

Compounds of Formula I may be used in combination with other drugs thatare used in the treatment/prevention/suppression or amelioration of thediseases or conditions for which compounds of Formula I are useful. Suchother drugs may be administered, by a route and in an amount commonlyused therefor, contemporaneously or sequentially with a compound ofFormula I. When a compound of Formula I is used contemporaneously withone or more other drugs, a pharmaceutical composition containing suchother drugs in addition to the compound of Formula I is preferred.Accordingly, the pharmaceutical compositions of the present inventioninclude those that also contain one or more other active ingredients, inaddition to a compound of Formula I. Examples of other activeingredients that may be combined with a compound of Formula I include,but are not limited to: antipsychotic agents, cognition enhancingagents, anti-migraine agents, anti-asthmatic agents, antiinflammatoryagents, anxiolytics, anti-Parkinson's agents, anti-epileptics, anorecticagents, serotonin reuptake inhibitors, and other anti-obesity agents, aswell as antidiabetic agents, lipid lowering agents, and antihypertensiveagents which may be administered separately or in the samepharmaceutical compositions.

The present invention also provides a method for the treatment orprevention of a CB1 receptor modulator mediated disease, which methodcomprises administration to a patient in need of such treatment or atrisk of developing a CB1 receptor modulator mediated disease of anamount of a CB1 receptor modulator and an amount of one or more activeingredients, such that together they give effective relief.

In a further aspect of the present invention, there is provided apharmaceutical composition comprising a CB1 receptor modulator and oneor more active ingredients, together with at least one pharmaceuticallyacceptable carrier or excipient.

Thus, according to a further aspect of the present invention there isprovided the use of a CB1 receptor modulator and one or more activeingredients for the manufacture of a medicament for the treatment orprevention of a CB1 receptor modulator mediated disease. In a further oralternative aspect of the present invention, there is therefore provideda product comprising a CB1 receptor modulator and one or more activeingredients as a combined preparation for simultaneous, separate orsequential use in the treatment or prevention of CB1 receptor modulatormediated disease. Such a combined preparation may be, for example, inthe form of a twin pack.

It will be appreciated that for the treatment or prevention of eatingdisorders, including obesity, bulimia nervosa and compulsive eatingdisorders, a compound of the present invention may be used inconjunction with other anorectic agents. The present invention alsoprovides a method for the treatment or prevention of eating disorders,which method comprises administration to a patient in need of suchtreatment an amount of a compound of the present invention and an amountof an anorectic agent, such that together they give effective relief.

Suitable anorectic agents of use in combination with a compound of thepresent invention include, but are not limited to, a minorex,amphechloral, amphetamine, benzphetamine, chlorphentermine, clobenzorex,cloforex, clominorex, clortermine, cyclexedrine, dexfenfluramine,dextroamphetamine, diethylpropion, diphemethoxidine, N-ethylamphetamine,fenbutrazate, fenfluramine, fenisorex, fenproporex, fludorex,fluminorex, furfurylmethylamphetamine, levamfetamine, levophacetoperane,mazindol, mefenorex, metamfepramone, methamphetamine,norpseudoephedrine, pentorex, phendimetrazine, phenmetrazine,phentermine, phenylpropanolamine, picilorex and sibutramine; andpharmaceutically acceptable salts thereof.

A particularly suitable class of anorectic agent are the halogenatedamphetamine derivatives, including chlorphentermine, cloforex,clortermine, dexfenfluramine, fenfluramine, picilorex and sibutramine;and pharmaceutically acceptable salts thereof

Particularly preferred halogenated amphetamine derivatives of use incombination with a compound of the present invention include:fenfluramine and dexfenfluramine, and pharmaceutically acceptable saltsthereof.

The present invention also provides a method for the treatment orprevention of obesity, which method comprises administration to apatient in need of such treatment an amount of a compound of the presentinvention and an amount of another agent useful in treating obesity andobesity-related conditions, such that together they give effectiverelief.

Suitable anti-obesity agents of use in combination with a compound ofthe present invention, include, but are not limited to:

-   -   (a) anti-diabetic agents such as (1) PPARγ agonists such as        glitazones (e.g. ciglitazone; darglitazone; englitazone;        isaglitazone (MCC-555); pioglitazone; rosiglitazone;        troglitazone; BRM49653; CLX-0921; 5-BTZD, and GW-0207,        LG-100641, and LY-300512, and the like and compounds disclosed        in WO97/10813, 97/27857, 97/28115, 97/28137, 97127847,        03/000685, and 03/027112; (2) biguanides such as buformin;        metformin; and phenformin, and the like; (3) protein tyrosine        phosphatase-IB (PTP-1B) inhibitors, such as those disclosed in        WO 03/032916, WO 03/032982; (4) sulfonylureas such as        acetohexamide; chlorpropamide; diabinese; glibenclamide;        glipizide; glyburide; glimepiride; gliclazide; glipentide;        gliquidone; glisolamide; tolazamide; and tolbutamide, and the        like; (5) meglitinides such as repaglinide, and nateglinide, and        the like; (6) alpha glucoside hydrolase inhibitors such as        acarbose; adiposine; camiglibose; emiglitate; miglitol;        voglibose; pradimicin-Q; salbostatin; CKD-711; MDL-25,637;        MDL-73,945; and MOR 14, and the like; (7) alpha-amylase        inhibitors such as tendamistat, trestatin, and A1-3688, and the        like; (8) insulin secreatagogues such as linogliride; and        A-4166, and the like; (9) fatty acid oxidation inhibitors, such        as clomoxir, and etomoxir, and the like; (10) A2 antagonists,        such as midaglizole; isaglidole; deriglidole; idazoxan; earoxan;        and fluparoxan, and the like; (11) insulin or insulin mimetics,        such as biota, LP-100, novarapid, insulin detemir, insulin        lispro, insulin glargine, insulin zinc suspension (lente and        ultralente); Lys-Pro insulin, GLP-1 (73-7) (insulintropin); and        GLP-1 (7-36)-NH₂), and the like; (12) non-thiazolidinediones        such as JT-501, and farglitazar (GW-2570/GI-262579), and the        like; (13) PPARouy dual agonists such as CLX-0940, GW-1536,        GW1929, GW-2433, KRP-297, L-796449, LR-90, MK-0767, SB 219994,        and reglitazar (JTT-501) and those disclosed in WO 99/16758, WO        99/19313, WO 99/20614, WO 99/38850, WO 00/23415, WO 00/23417, WO        00/23445, WO 00/50414, WO 01/00579, WO 01/79150, WO 02/062799,        WO 03/016265, WO 03/033481, WO 03/033450, WO 03/033453 WO        03/043985; and (14) other insulin sensitizing drugs; (15) VPAC2        receptor agonists; (16) GLK modulators, such as those disclosed        in WO 03/015774; (17) retinoid modulators such as those        disclosed in WO 03/000249; (18) GSK 3beta/GSK 3 inhibitors such        as        4-[2-(2-bromophenyl)-4-(4-fluorophenyl-1H-imidazol-5-yl]pyridine        and those compounds disclosed in WO 03/037869, WO 03/03877, WO        03/037891, WO 03/024447, and the like; (19) glycogen        phosphorylase (HGLPa) inhibitors, such as those disclosed in WO        03/037864; (20) ATP consumption promotors such as those        disclosed in WO 03/007990; (21) TRB3 inhibitors, (22) vanilloid        receptor ligands such as those disclosed in WO 03/049702, (23)        hypoglycemic agnets such as those disclosed in WO 03/015781, WO        03/040114, (24) glycogen synthase kinase 3 inhibitors such as        those disclosed in WO 03/035663, and    -   (b) lipid lowering agents such as (1) bile acid sequestrants        such as, cholestyramine, colesevelem, colestipol,        dialkylaminoalkyl derivatives of a cross-linked dextran;        Colestid®; LoCholest®; and Questran®, and the like; (2) HMG-CoA        reductase inhibitors such as atorvastatin, itavastatin,        fluvastatin, lovastatin, pravastatin, rivastatin, rosuvastatin,        simvastatin, and ZD-4522, and the like and compounds disclosed        in WO 03/033481; (3) HMG-CoA synthase inhibitors; (4)        cholesterol absorption inhibitors such as stanol esters,        beta-sitosterol, sterol glycosides such as tiqueside; and        azetidinones such as ezetimibe, and the like; (5) acyl coenzyme        A-cholesterol acyl transferase (ACAT) inhibitors such as        avasimibe, eflucimibe, KY505, SMP 797, and the like; (6) CETP        inhibitors such as JIT 705, torcetrapib, CP 532,632, BAY63-2149,        SC 591, SC 795, and the like; (7) squalene synthetase        inhibitors; (8) anti-oxidants such as probucol, and the        like; (9) PPARα agonists such as beclofibrate, benzafibrate,        ciprofibrate, clofibrate, etofibrate, fenofibrate, gemcabene,        and gemfibrozil, GW 7647, BM 170744, LY518674; and other fibric        acid derivatives, such as Atromid®, Lopid® and Tricor®, and        those disclosed in WO 03/043997 and the like; (10) FXR receptor        modulators such as GW 4064, SR 103912, and the like; (11) LXR        receptor modulators such as GW 3965, T9013137, and XIC0179628,        and the like; (12) lipoprotein synthesis inhibitors such as        niacin; (13) renin angiotensin system inhibitors; (14) PPAR δ        partial agonists, such as those disclosed in WO 03/024395; (15)        bile acid reabsorption inhibitors, such as BARI 1453, SC435,        PHA384640, S8921, AZD7706, and the like; (16) PPAR⁸ agonists        such as GW 501516, and GW 590735, and the like, such as those        disclosed in WO97/28149, WO 01/79197, WO 02/14291, WO 02/46154,        WO 02/46176, WO 02/076957, WO 03/016291, WO 03/033493; (17)        triglyceride synthesis inhibitors; (18) microsomal triglyceride        transport (MTTP) inhibitors, such as inplitapide, LAB687, and        CP346086, and the like; (19) transcription modulators; (20)        squalene epoxidase inhibitors; (21) low density lipoprotein        (LDL) receptor inducers; (22) platelet aggregation        inhibitors; (23) 5-LO or FLAP inhibitors; and (24) niacin        receptor agonists; (25) PPAR modulators such as those disclosed        in WO 99/07357, WO 99/11255, WO 9912534, WO 99/15520, WO        99/46232, WO 00/12491, WO 00/23442, WO 01/25181, WO 01/79150, WO        02/79162, WO 02/102780, WO 02/081428, WO 03/016265, WO        03/033453, WO 03/042194, (26) niacin-bound chromium, as        disclosed in WO 03/039535; (27) substituted acid derivatives        disclosed in WO 03/040114; (28) apolipoprotein B inhibitors such        as those disclosed in WO 02/090347, WO 02/28835, WO 03/045921;        and    -   (c) anti-hypertensive agents such as (1) diuretics, such as        thiazides, including chlorthalidone, chlorthiazide,        dichlorophenamide, hydroflumethiazide, indapamide, and        hydrochlorothiazide; loop diuretics, such as bumetamide,        ethacrynic acid, furosemide, and torsemide; potassium sparing        agents, such as amiloride, and triamterene; and aldosterone        antagonists, such as spironolactone, epirenone, and the        like; (2) beta-adrenergic blockers such as acebutolol, atenolol,        betaxolol, bevantolol, bisoprolol, bopindolol, carteolol,        carvedilol, celiprolol, esmolol, indenolol, metaprolol, nadolol,        nebivolol, penbutolol, pindolol, propanolol, sotalol,        tertatolol, tilisolol, and timolol, and the like; (3) calcium        channel blockers such as amlodipine, aranidipine, azelnidipine,        barnidipine, benidipine, bepridil, cinaldipine, clevidipine,        diltiazem, efonidipine, felodipine, gallopamil, isradipine,        lacidipine, lemildipine, lercanidipine, nicardipine, nifedipine,        nilvadipine, nimodepine, nisoldipine, nitrendipine, manidipine,        pranidipine, and verapamil, and the like; (4) angiotensin        converting enzyme (ACE) inhibitors such as benazepril;        captopril; cilazapril; delapril; enalapril; fosinopril;        imidapril; losinopril; moexipril; quinapril; quinaprilat;        ramipril; perindopril; perindropril; quanipril; spirapril;        tenocapril; trandolapril, and zofenopril, and the like; (5)        neutral endopeptidase inhibitors such as omapatrilat, cadoxatril        and ecadotril, fosidotril, sampatrilat, AVE7688, ER4030, and the        like; (6) endothelin antagonists such as tezosentan, A308165,        and YM62899, and the like; (7) vasodilators such as hydralazine,        clonidine, minoxidil, and nicotinyl alcohol, and the like; (8)        angiotensin II receptor antagonists such as candesartan,        eprosartan, irbesartan, losartan, pratosartan, tasosartan,        telmisartan, valsartan, and EXP-3137, F16828K, and RNH6270, and        the like; (9) ou/p adrenergic blockers as nipradilol, arotinolol        and amosulalol, and the like; (10) alpha 1 blockers, such as        terazosin, urapidil, prazosin, bunazosin, trimazosin, doxazosin,        naftopidil, indoramin, WHIP 164, and XEN010, and the like; (11)        alpha 2 agonists such as lofexidine, tiamenidine, moxonidine,        rilmenidine, tizanidine, and guanobenz, and the like; and (12)        aldosterone inhibitors, and the like; (13) angiopoietin-2        binding agents such as those disclosed in WO 03/030833, and    -   (d) anti-obesity agents, such as (1) 5HT (serotonin) transporter        inhibitors, such as paroxetine, fluoxetine, fenfluramine,        fluvoxamine, sertraline, and imipramine, and those disclosed in        WO 03/00663; (2) NE (norepinephrine) transporter inhibitors,        such as GW 320659, despiramine, talsupram, and nornifensine; (3)        CB1 (cannabinoid-1 receptor) antagonist/inverse agonists, such        as rimonabant (Sanofi Synthelabo), SR-147778 (Sanofi        Synthelabo), BAY 65-2520 (Bayer), and SLV 319 (Solvay), and        those disclosed in U.S. Pat. Nos. 4,973,587, 5,013,837,        5,081,122, 5,112,820, 5,292,736, 5,532,237, 5,624,941,        6,028,084, and 6,509,367; and WO 96/33159, WO97/29079,        WO98/31227, WO 98/33765, WO98/37061, WO98/41519, WO98/43635,        WO98/43636, WO99/02499, WO00/10967, WO00/10968, WO 01/09120, WO        01/58869, WO 01/64632, WO 01/64633, WO 01/64634, WO 01/0700, WO        01/96330, WO 02/076949, WO 03/006007, WO 03/007887, WO        03/020217, WO 03/026647, WO 03/026648, WO 03/027069, WO        03/027076, WO 03/027114, WO 03/037332, WO 03/040107, WO        03/042174; and EPO No. EP-658546; (4) ghrelin antagonists, such        as those disclosed in WO 01/87335, and WO 02/08250; (5) H3        (histamine H3) antagonist/inverse agonists, such as        thioperamide, 3-(1H-imidazol-4-yl)propyl        N-(4-pentenyl)carbamate), clobenpropit, iodophenpropit,        imoproxifan, GT2394 (Gliatech), and A331440, and those disclosed        in WO 02/15905; and O-[3-(1H-imidazol-4-yl)propanol]carbamates        (Kiec-Kononowicz, K. et al., Pharmazie, 55:349-55 (2000)),        piperidine-containing histamine H3-receptor antagonists        (Lazewska, D. et al., Pharmazie, 56:927-32 (2001), benzophenone        derivatives and related compounds (Sasse, A. et al., Arch.        Pharm.(Weinheim) 334:45-52 (2001)), substituted        N-phenylcarbamates (Reidemeister, S. et al., Pharmazie, 55:83-6        (2000)), and proxifan derivatives (Sasse, A. et al., J. Med.        Chem. 43:3335-43 (2000)) and histamine H3 receptor modulators        such as those disclosed in WO 03/024928, WO 03/024929, WO        03/044059 (6) melanin-concentrating hormone 1 receptor (MCH1R)        antagonists, such as T-226296 (Takeda), SNP-7941 (Synaptic), and        those disclosed WO 01/21169, WO 01/82925, WO 01/87834, WO        02/051809, WO 02/06245, WO 02/076929, WO 02/076947, WO 02/04433,        WO 02/51809, WO 02/083134, WO 02/094799, WO 03/004027, WO        03/13574, WO 03/15769, WO 03/028641, WO 03/035624, WO 03/033476,        WO 03/033480, WO 03/35055, WO 03/047568, WO 03/045918; and        Japanese Patent Application Nos. JP 13226269, and JP        1437059; (7) MCH2R (melanin concentrating hormone 2R)        agonist/antagonists; (8) NPY1 (neuropeptide Y Y1) antagonists,        such as BIBP3226, J-115814, B1BO 3304, LY-357897, CP-671906, and        GI-264879A; and those disclosed in U.S. Pat. No. 6,001,836; and        WO 96/14307, WO 01/23387, WO 99/51600, WO 01/85690, WO 01/85098,        WO 01/85173, and WO 01/89528; (9) NPY5 (neuropeptide Y Y5)        antagonists, such as 152,804, GW-569180A, GW-594884A,        GW-587081×, GW-548118×; FR 235,208; FR226928, FR 240662,        FR252384; 1229U91, GI-264879A, CGP71683A, LY-377897, LY366377,        PD-160170, SR-120562A, SR-120819A, JCF-104, and H409/22; and        those compounds disclosed in U.S. Pat. Nos. 6,140,354,        6,191,160, 6,258,837, 6,313,298, 6,326,375, 6,329,395,        6,335,345, 6,337,332, 6,329,395, and 6,340,683; European Patent        Nos. EP-01010691, EP-01044970, EP 1306085; and PCT Publication        Nos. WO 97/19682, WO 97/20820, WO 97/20821, WO 97/20822, WO        97/20823, WO 98/27063, WO 00/107409, WO 00/185714, WO 00/185730,        WO 00/64880, WO 00/68197, WO 00/69849, WO 01/09120, WO 01/14376,        WO 01/85714, WO 01/85730, WO 01/07409, WO 01/02379, WO 01/02379,        WO 01/23388, WO 01/23389, WO 01/44201, WO 01/62737, WO 01/62738,        WO 01/09120, WO 02/20488, WO 02/22592, WO 02/48152, WO 02/49648,        WO 02/051806, WO 02/094789, WO 03/009845, WO 03/014083, WO        03/022849, WO 03/028726; and Norman et al., J. Med. Chem.        43:4288-4312 (2000); (10) leptin, such as recombinant human        leptin (PEG-OB, Hoffman La Roche) and recombinant methionyl        human leptin (Amgen); (11) leptin derivatives, such as those        disclosed in U.S. Pat. Nos. 5,552,524; 5,552,523; 5,552,522;        5,521,283; and WO 96/23513; WO 96/23514; WO 96/23515; WO        96/23516; WO 96/23517; WO 96/23518; WO 96/23519; and WO        96/23520; (12) opioid antagonists, such as nalmefene (Revex®),        3-methoxynaltrexone, naloxone, and naltrexone; and those        disclosed in WO 00/21509; (13) orexin antagonists, such as        SB-334867-A; and those disclosed in WO 99/09024, WO 99/58533, WO        01/96302, WO 01/68609, WO 02/44172, WO 02/51232, WO 02/51838, WO        02/089800, WO 02/090355, WO 03/023561, WO 03/032991, WO        03/037847, WO 03/041711; (14) BRS3 (bombesin receptor subtype 3)        agonists; (15) CCK-A (cholecystokinin-A) agonists, such as AR-R        15849, GI 181771, JMV-180, A-71378, A-71623 and SR¹⁴⁶¹³¹, and        those disclosed in U.S. Pat. No. 5,739,106; (16) CNTIF (ciliary        neurotrophic factors), such as GI-181771 (Glaxo-SmithKline);        SR146131 (Sanofi Synthelabo); butabindide; and PD 170,292, PD        149164 (Pfizer); (17) CNTF derivatives, such as axokine        (Regeneron); and those disclosed in WO 94/09134, WO 98/22128,        and WO 99/43813; (18) GHS (growth hormone secretagogue receptor)        agonists, such as NN703, hexarelin, MK-0677, SM-130686,        CP-424,391, L-692,429 and L-163,255, and those disclosed in U.S.        Pat. No. 6,358,951, U.S. Patent Application Nos. 2002/049196 and        2002/022637; and WO 01/56592, and WO 02/32888; (19) 5HT2c        (serotonin receptor 2c) modulators, such as BVT933, DPCA37215,        IK264; PNU 22394; WAY161503, R-1065, and YM 348; and those        disclosed in U.S. Pat. No. 3,914,250; and WO 01/66548, WO        02/10169, WO 02/36596, WO 02/40456, and WO 02/40457. WO        02/44152, WO 02/48124, WO 02/51844, WO 03/033479 and the        like; (20) Mc3r (melanocortin 3 receptor) agonists; (21) Mc4r        (melanocortin 4 receptor) agonists, such as CHIR86036 (Chiron);        ME-10142, ME-10145, and HS-131 (Melacure), and those disclosed        in WO 99/64002, WO 00/74679, WO 01/991752, WO 01/0125192, WO        01/52880, WO 01/74844, WO 01/70708, WO 01/70337, WO 01/91752, WO        02/059095, WO 02/059107, WO 02/059108, WO 02/059117, WO        02/06276, WO 02/12166, WO 02/11715, WO 02/12178, WO 02/15909, WO        02/38544, WO 02/068387, WO 02/068388, WO 02/067869, WO        02/081430, WO 03/06604, WO 03/007949, WO 03/009847, WO        03/009850, WO 03/013509, WO 03/031410, WO 03/040117, WO        03/040118; (22) monoamine reuptake inhibitors, such as        sibutratmine (Meridia®/Reductil®) and salts thereof, and those        compounds disclosed in U.S. Pat. Nos. 4,746,680, 4,806,570, and        5,436,272, and U.S. Patent Publication No. 2002/0006964, and WO        01/27068, and WO 01/62341; (23) serotonin reuptake inhibitors,        such as dexfenfluramine, fluoxetine, and those in U.S. Pat. No.        6,365,633, and WO 01/27060, and WO 01/162341; (24) GLP-1        (glucagon-like peptide 1) agonists; (25) Topiramate        (Topimax®); (26) phytopharm compound 57 (CP 644,673); (27) ACC2        (acetyl-CoA carboxylase-2) inhibitors; (28) β3 (beta adrenergic        receptor 3) agonists, such as AD9677/TAK677 (Dainippon/Takeda),        CL-316,243, SB 418790, BRL-37344, L-796568, BMS-196085,        BRL-35135A, CGP12177A, BTA-243, GW 427353, Trecadrine,        ZenecaD7114, N-5984 (Nisshin Kyorin), LY-377604 (Lilly), and SR        59119A, and those disclosed in U.S. Pat. No. 5,705,515, U.S.        Pat. No. 5,451,677; and WO94/18161, WO95/29159, WO97/46556,        WO98/04526 and WO98/32753, WO 01/74782, WO 02/32897, WO        03/014113, WO 03/016276, WO 03/016307, WO 03/024948, WO        03/024953, WO 03/037881, WO 03/0946, WO 03/044016, WO        03/044017; (29) DGAT1 (diacylglycerol acyltransferase 1)        inhibitors; (30) DGAT2 (diacylglycerol acyltransferase        2)inhibitors; (31) FAS (fatty acid synthase) inhibitors, such as        Cerulenin and C75; (32) PDE (phosphodiesterase) inhibitors, such        as theophylline, penitoxifylline, zaprinast, sildenafil,        amrinone, milrinone, cilostamide, rolipram, and cilomilast, as        well as those described in WO 03/037432, WO 03/037899; (33)        thyroid hormone, agonists, such as KB-2611 (KaroBioBMS), and        those disclosed in WO 02/15845; and Japanese Patent Application        No. JP 2000256190; (34) UCP-1 (uncoupling protein 1), 2, or 3        activators, such as phytanic acid,        4-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-napthalenyl)-1-propenyl]benzoic        acid (TTNPB), and retinoic acid; and those disclosed in WO        99/00123; (35) acyl-estrogens, such as oleoyl-estrone, disclosed        in del Mar-Grasa, M. et al., Obesity Research, 9:202-9        (2001); (36) glucocorticoid antagonists; (37) 11β HSD-1 (11-beta        hydroxy steroid dehydrogenase type 1) inhibitors, such as BVT        3498, BVT 2733,        3-(1-adamantyl)-4-ethyl-5-(ethylthio)-4H-1,2,4-triazole,        3-(1-adamantyl)-5-(3,4,5-trimethoxyphenyl)₄-methyl-4H-1,2,4-triazole,        3-adamantanyl-4,5,6,7,8,9,10,11,12,3a-decahydro-1,2,4-triazolo[4,3-a][11]annulene,        and those compounds disclosed in WO 01/90091, WO 01/90090, WO        01/90092 and WO 02/072084; (38) SCD-1 (stearoyl-CoA        desaturase-1) inhibitors; (39) dipeptidyl peptidase IV (DP-IV)        inhibitors, such as isoleucine thiazolidide, valine pyrrolidide,        NVP-DPP728, LAF237, P93/01, TSL 225, TMC-2A/2B/2C, FE 999011,        P9310/K364, VIP 0177, SDZ 274444; and the compounds disclosed in        WO 02/083128, WO 02/062764, WO 03/000180, WO 03/000181, WO        03/000250, WO 03/002530, WO 03/002531, WO 03/002553, WO        03/002593, WO 03/004498, WO 03/004496, WO 03/017936, WO        03/024942, WO 03/024965, WO 03/033524, WO 03/035057, WO        03/03567, WO 03/037327 and EP 1 258 476; (40) lipase inhibitors,        such as tetrahydrolipstatin (orlistat/Xenical®), Triton WR1339,        RHC80267, lipstatin, teasaponin, and diethylumbelliferyl        phosphate, FL-386, WAY-121898, Bay-N-3176, valilactone,        esteracin, ebelactone A, ebelactone B, and RHC 80267, and those        disclosed in WO 01/77094, and U.S. Pat. Nos. 4,598,089,        4,452,813, 5,512,565, 5,391,571, 5,602,151, 4,405,644,        4,189,438, and 4,242,453; (41) fatty acid transporter        inhibitors; (42) dicarboxylate transporter inhibitors; (43)        glucose transporter inhibitors; and (44) phosphate transporter        inhibitors; (45) anorectic bicyclic compounds such as 1426        (Aventis) and 1954 (Aventis), and the compounds disclosed in WO        00/18749, WO 01/32638, WO 01/62746, WO 01/62747, and WO        03/015769; (46) peptide YY and PYY agonists such as those        disclosed in WO 03/026591; (47) lipid metabolism modulators such        as maslinic acid, erythrodiol, ursolic acid uvaol, betulinic        acid, betulin, and the like and compounds disclosed in WO        03/011267; (48) transcription factor modulators such as those        disclosed in WO 03/026576; (49) Mc5r (melanocortin 5 receptor)        modulators, such as those disclosed in WO 97/19952, WO 00/15826,        WO 00/15790, U.S. 20030092041, (50) appetite suppressants such        as those disclosed in WO 03/040107, (51) SHT 6 receptor        modulators, such as those disclosed in WO 03/030901, WO        03/035061, WO 03/039547, and the like; (52) 5HT1a modulators        such as those disclosed in WO 03/031439, and the like.

Specific NPY5 antagonists of use in combination with a compound of thepresent invention are selected from the group consisting of:

-   (1) 3-oxo-N-(5-phenyl-2-pyrazinyl)-spiro[isobenzofuran-1(3H),    4′-piperidine]-1′-carboxamide,-   (2)    3-oxo-N-(7-trifluoromethylpyrido[3,2-b]pyridin-2-yl)spiro-[isobenzofuran-1(3H),    4′-piperidine]-1′-carboxamide,-   (3)    N-[5-(3-fluorophenyl)-2-pyrimidinyl]-3-oxospiro-[isobenzofuran-1(3H),    4′-piperidine]-1′-carboxamide,-   (4) trans-3′-oxo-N-(5-phenyl-2-pyrimidinyl)spiro[cyclohexane-1,1    (3′H)-isobenzofuran]-4-carboxamide,-   (5)    trans-3′-oxo-N-[1-(3-quinolyl)-4-imidazolyl]spiro[cyclohexane-1,1′(3′H)-isobenzofuran]-4-carboxamide,-   (6)    trans-3-oxo-N-(5-phenyl-2-pyrazinyl)spiro[4-azaiso-benzofuran-1(3H),    1-cyclohexane]-4′-carboxamide,-   (7)    trans-N-[5-(3-fluorophenyl)-2-pyrimidinyl]-3-oxospiro[5-azaisobenzofuran-1(3H),    1′-cyclohexane]-4′-carboxamide,-   (8)    trans-N-[5-(2-fluorophenyl)-2-pyrimidinyl]-3-oxospiro[5-azaisobenzofuran-1(3H),    1′-cyclohexane]-4′-carboxamide,-   (9)    trans-N-[1-(3,5-difluorophenyl)-4-imidazolyl]-3-oxospiro[7-azaisobenzofuran-1(3H),    1′-cyclohexane]-4′-carboxamide,-   (10)    trans-3-oxo-N-(1-phenyl-4-pyrazolyl)spiro[4-azaisobenzofuran-1(3H),    1′-cyclohexane]-4′-carboxamide,-   (11)    trans-N-[1-(2-fluorophenyl)-3-pyrazolyl]-3-oxospiro[6-azaisobenzofuran-1    (3H), 1′-cyclohexane]-4′-carboxaamide,-   (12)    trans-3-oxo-N-(1-phenyl-3-pyrazolyl)spiro[6-azaisobenzofuran-1(3H),    1′-cyclohexane]-4′-carboxamide,-   (13)    trans-3-oxo-N-(2-phenyl-1,2,3-triazol-4-yl)spiro[6-azaisobenzofuran-1(3H),    1′-cyclohexane]-4′-carboxamide,    and pharmaceutically acceptable salts and esters thereof.

“Obesity” is a condition in which there is an excess of body fat. Theoperational definition of obesity is based on the Body Mass Index (BM),which is calculated as body weight per height in meters squared kg/m²).“Obesity” refers to a condition whereby an otherwise healthy subject hasa Body Mass Index (BM) greater than or equal to 30 kg/m², or a conditionwhereby a subject with at least one co-morbidity has a BMI greater thanor equal to 27 kg/m². An “obese subject” is an otherwise healthy subjectwith a Body Mass Index (BM) greater than or equal to 30 kg/m² or asubject with at least one co-morbidity with a BMI greater than or equalto 27 kg/m². A “subject at risk for obesity” is an otherwise healthysubject with a BMI of 25 kg/m2 to less than 30 kg/m² or a subject withat least one co-morbidity with a BMI of 25 kg/m² to less than 27 kg/m².

The increased risks associated with obesity occur at a lower Body MassIndex (BMI) in Asians. In Asian countries, including Japan, “obesity”refers to a condition whereby a subject with at least oneobesity-induced or obesity-related co-morbidity that requires weightreduction or that would be improved by weight reduction, has a BMIgreater than or equal to 25 kg/m². In Asian countries, including Japan,an “obese subject” refers to a subject with at least one obesity-inducedor obesity-related co-morbidity that requires weight reduction or thatwould be improved by weight reduction, with a BMI greater than or equalto 25 kg/m². In Asian countries, a “subject at risk of obesity” is asubject with a BMI of greater than 23 kg/m² to less than 25 kg/m².

As used herein, the term “obesity” is meant to encompass all of theabove definitions of obesity.

Obesity-induced or obesity-related co-morbidities include, but are notlimited to, diabetes, non-insulin dependent diabetes mellitus—type 2,impaired glucose tolerance, impaired fasting glucose, insulin resistancesyndrome, dyslipidemia, hypertension, hyperuricacidemia, gout, coronaryartery disease, myocardial infarction, angina pectoris, sleep apneasyndrome, Pickwickian syndrome, fatty liver; cerebral infarction,cerebral thrombosis, transient ischemic attack, orthopedic disorders,arthritis deformans, lumbodynia, emmeniopathy, and infertility. Inparticular, co-morbidities include: hypertension, hyperlipidemia,dyslipidemia, glucose intolerance, cardiovascular disease, sleep apnea,diabetes mellitus, and other obesity-related conditions.

“Treatment” (of obesity and obesity-related disorders) refers to theadministration of the compounds of the present invention to reduce ormaintain the body weight of an obese subject. One outcome of treatmentmay be reducing the body weight of an obese subject relative to thatsubject's body weight immediately before the administration of thecompounds of the present invention. Another outcome of treatment may bepreventing body weight regain of body weight previously lost as a resultof diet, exercise, or pharmacotherapy. Another outcome of treatment maybe decreasing the occurrence of and/or the severity of obesity-relateddiseases. The treatment may suitably result in a reduction in food orcalorie intake by the subject, including a reduction in total foodintake, or a reduction of intake of specific components of the diet suchas carbohydrates or fats; and/or the inhibition of nutrient absorption;and/or the inhibition of the reduction of metabolic rate; and in weightreduction in patients in need thereof. The treatment may also result inan alteration of metabolic rate, such as an increase in metabolic rate,rather than or in addition to an inhibition of the reduction ofmetabolic rate; and/or in minimization of the metabolic resistance thatnormally results from weight loss.

“Prevention” (of obesity and obesity-related disorders) refers to theadministration of the compounds of the present invention to reduce ormaintain the body weight of a subject at risk of obesity. One outcome ofprevention may be reducing the body weight of a subject at risk ofobesity relative to that subject's body weight immediately before theadministration of the compounds of the present invention. Anotheroutcome of prevention may be preventing body weight regain of bodyweight previously lost as a result of diet, exercise, orpharmacotherapy. Another outcome of prevention may be preventing obesityfrom occurring if the treatment is administered prior to the onset ofobesity in a subject at risk of obesity. Another outcome of preventionmay be decreasing the occurrence and/or severity of-obesity-relateddisorders if the treatment is administered prior to the onset of obesityin a subject at risk of obesity. Moreover, if treatment is commenced inalready obese subjects, such treatment may prevent the occurrence,progression or severity of obesity-related disorders, such as, but notlimited to, arteriosclerosis, Type II diabetes, polycystic ovariandisease, cardiovascular diseases, osteoarthritis, dermatologicaldisorders, hypertension, insulin resistance, hypercholesterolemia,hypertriglyceridemia, and cholelithiasis.

The obesity-related disorders herein are associated with, caused by, orresult from obesity. Examples of obesity-related disorders includeovereating and bulimia, hypertension, diabetes, elevated plasma insulinconcentrations and insulin resistance, dyslipidemias, hyperlipidemia,endometrial, breast, prostate and colon cancer, osteoarthritis,obstructive sleep apnea, cholelithiasis, gallstones, heart disease,abnormal heart rhythms and arrythmias, myocardial infarction, congestiveheart failure, coronary heart disease, sudden death, stroke, polycysticovarian disease, craniopharyngioma, the Prader-Willi Syndrome,Frohlich's syndrome, OH-deficient subjects, normal variant shortstature, Turner's syndrome, and other pathological conditions showingreduced metabolic activity or a decrease in resting energy expenditureas a percentage of total fat-free mass, e.g, children with acutelymphoblastic leukemia. Further examples of obesity-related disordersare metabolic syndrome, also known as syndrome X, insulin resistancesyndrome, sexual and reproductive dysfunction, such as infertility,hypogonadism in males and hirsutism in females, gastrointestinalmotility disorders, such as obesity-related gastro-esophageal reflux,respiratory disorders, such as obesity-hypoventilation syndrome(Pickwickian syndrome), cardiovascular disorders, inflammation, such assystemic inflammation of the vasculature, arteriosclerosis,hypercholesterolemia, hyperuricaemia, lower back pain, gallbladderdisease, gout, and kidney cancer. The compounds of the present inventionare also useful for reducing the risk of secondary outcomes of obesity,such as reducing the risk of left ventricular hypertrophy.

The term “diabetes,” as used herein, includes both insulin-dependentdiabetes mellitus (i.e., IDDM, also known as type I diabetes) andnon-insulin-dependent diabetes mellitus (i.e., NIDDM, also known as TypeIt diabetes. Type I diabetes, or insulin-dependent diabetes, is theresult of an absolute deficiency of insulin, the hormone which regulatesglucose utilization. Type II diabetes, or insulin-independent diabetes(i.e., non-insulin-dependent diabetes mellitus), often occurs in theface of normal, or even elevated levels of insulin and appears to be theresult of the inability of tissues to respond appropriately to insulin.Most of the Type II diabetics are also obese. The compounds of thepresent invention are useful for treating both Type I and Type IIdiabetes. The compounds are especially effective for treating Type IIdiabetes. The compounds of the present invention are also useful fortreating and/or preventing gestational diabetes mellitus.

It will be appreciated that for the treatment or prevention of migraine,a compound of the present invention may be used in conjunction withother anti-migraine agents, such as ergotamines or 5-HIT₁ agonists,especially sumatriptan, naratriptan, zolmatriptan or rizatriptan.

It will be appreciated that for the treatment of depression or anxiety,a compound of the present invention may be used in conjunction withother anti-depressant or anti-anxiety agents.

Suitable classes of anti-depressant agents include norepinephrinereuptake inhibitors, selective serotonin reuptake inhibitors (SSRIs),monoamine oxidase inhibitors (MAOIs), reversible inhibitors of monoamineoxidase (RIMAs), serotonin and noradrenaline reuptake inhibitors(SNRIs), corticotropin releasing factor (CRF) antagonists,α-adrenoreceptor antagonists, neurokinin-1 receptor antagonists andatypical anti-depressants.

Suitable norepinephrine reuptake inhibitors include tertiary aminetricyclics and secondary amine tricyclics. Suitable examples of tertiaryamine tricyclics include: amitriptyline, clomipramine, doxepin,imipramine and trimipramine, and pharmaceutically acceptable saltsthereof. Suitable examples of secondary amine tricyclics include:amoxapine, desipramine, maprotiline, nortriptyline and protriptyline,and pharmaceutically acceptable salts thereof.

Suitable selective serotonin reuptake inhibitors include: fluoxetine,fluvoxamine, paroxetine, imipramine and sertraline, and pharmaceuticallyacceptable salts thereof.

Suitable monoamine oxidase inhibitors include: isocarboxazid,phenelzine, tranylcypromine and selegiline, and pharmaceuticallyacceptable salts thereof. Suitable reversible inhibitors of monoamineoxidase include: moclobemide, and pharmaceutically acceptable saltsthereof.

Suitable serotonin and noradrenaline reuptake inhibitors of use in thepresent invention include: venlafaxine, and pharmaceutically acceptablesalts thereof.

Suitable CRF antagonists include those compounds described inInternational Patent Specification Nos. WO 94/13643, WO 94/13644, WO94/13661, WO 94/13676 and WO 94/13677.

Suitable neurokinin-1 receptor antagonists may be peptidal ornon-peptidal in nature, however, the use of a non-peptidal neurokinin-1receptor antagonist is preferred. In a preferred embodiment, theneurokinin-1 receptor antagonist is a CNS-penetrant neurokinin-1receptor antagonist. In addition, for convenience the use of an orallyactive neurokinin-1 receptor antagonist is preferred. To facilitatedosing, it is also preferred that the neurokinin-1 receptor antagonistis a long acting neurokinin-1 receptor antagonist. An especiallypreferred class of neurokinin-1 receptor antagonists of use in thepresent invention are those compounds which are orally active and longacting. Neurokinin-1 receptor antagonists of use in the presentinvention are fully described, for example, in U.S. Pat. Nos. 5,162,339,5,232,929, 5,242,930, 5,373,003, 5,387,595, 5,459,270, 5,494,926,5,496,833, 5,637,699; European Patent Publication Nos. EP 0 360 390, 0394 989, 0 428 434, 0 429 366, 0 430 771, 0 436 334, 0 443 132, 0 482539, 0 498 069, 0 499 313, 0 512 901, 0 512 902, 0 514 273, 0 514 274,0514 275, 0514 276, 0 515 681, 0 517 589, 0 520 555, 0 522 808, 0 528495, 0 532 456, 0 533 280, 0 536 817, 0 545 478, 0 558 156, 0 577 394, 0585 913, 0 590 152, 0 599 538, 0 610 793, 0 634 402, 0 686 629, 0 693489, 0 694 535, 0 699 655, 0 699 674, 0 707 006, 0 708 101, 0 709 375, 0709 376, 0 714 891, 0 723 959, 0 733 632 and 0 776 893; PCTInternational Patent Publication Nos. WO 90/05525, 90/05729, 91/09844,91/18899, 92/01688, 92/06079, 92/12151, 92/15585, 92/17449, 92/20661,92/20676, 92/21677, 92/22569, 93/00330, 93/00331, 93/01159, 93/01165,93/01169, 93/01170, 93/06099, 93/09116, 93/10073, 93/14084, 93/14113,93/18023, 93/19064, 93/21155, 93/21181, 93/23380, 93/24465, 94/00440,94/01402, 94/02461, 94/02595, 94/03429, 94/03445, 94/04494, 94/04496,94/05625, 94/07843, 94/08997, 94/10165, 94/10167, 94/10168, 94/10170,94/11368, 94/13639, 94/13663, 94/14767, 94/15903, 94/19320, 94/19323,94/20500, 94/26735, 94/26740, 94/29309, 95/02595, 95/04040, 95/04042,95/06645, 95/07886, 95/07908, 95/08549, 95/11880, 95/14017, 95/15311,95/16679, 95/17382, 95/18124, 95/18129, 95/19344, 95/20575, 95/21819,95/22525, 95/23798, 95/26338, 95/28418, 95/30674, 95/30687, 95/33744,96/05181, 96/05193, 96/05203, 96/06094, 96/07649, 96/10562, 96/16939,96/18643, 96/20197, 96/21661, 96/29304, 96/29317, 96/29326, 96/29328,96/31214, 96/32385, 96/37489, 97/01553, 97/01554, 97/03066, 97/08144,97/14671, 97/17362, 97/18206, 97/19084, 97/19942, 97/21702, 97/49710,98/24438-98/24441, 98/24442-98/24445, 02/16343, and 02/16344; and inBritish Patent Publication Nos. 2 266 529, 2 268 931, 2 269 170, 2 269590, 2 271 774, 2 292 144, 2 293 168, 2 293 169, and 2 302 689.

Specific neurokinin-1 receptor antagonists of use in the presentinvention include:

-   (1)    (±)-(2R3R,2S3S)-N-{[2-cyclopropoxy-5-(trifluoromethoxy)-phenyl]methyl}-2-phenylpiperidin-3-amine;-   (2)    2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3(S)-(4-fluorophenyl)-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)morpholine;-   (3)    2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)-3-(S)-phenyl-morpholine;-   (4)    2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)-3-(S)-phenyl-morpholine;-   (5)    2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)morpholine;-   (6)    2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(5-N,N-dimethylamino)methyl-1,2,3-triazol-4-yl)methyl-3-(S)-phenylmorpholine;-   (7)    2-(R)-(1-R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(5-(N,N-dimethylamino)methyl-1,2,3-triazol-4-yl)methyl-3-(S)-(4-fluorophenyl)morpholine;-   (8)    (3S,3R,6S)-3-[2-cyclopropoxy-5-(trifluoromethoxy)phenyl]-3-6-phenyl-1-oxa-7-aza-spiro[4.5]decane;-   (9)    (3R,5R,6S)-3-[2-cyclopropoxy-5-(trifluoromethoxy)phenyl]-6-phenyl-1-oxa-7-aza-spiro[4.5]decane;-   (10)    2-(R)-(1-(S)-(3,5-bis(trifluoromethyl)phenyl)-2-hydroxyethoxy)-3-(S)-(4-fluorophenyl)-4-(1,2,4-triazol-3-yl)methylmorpholine;-   (11)    2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4(3-(4-monophosphoryl-5-oxo-1H-1,2,4-triazolo)methyl)morpholine;-   (12)    2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(1-monophosphoryl-5-oxo-1H-1,2,4-triazolo)methyl)morpholine;-   (13)    2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(2-monophosphoryl-5-oxo-1H-1,2,4-triazolo)methyl)morpholine;-   (14)    2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(5-oxyphosphoryl-1H-1,2,4-triazolo)methyl)morpholine;-   (15)    2-(S)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(1-monophosphoryl-5-oxo-4H-1,2,4-triazolo)methyl)morpholine;-   (16)    2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(4-N,N-dimethylaminobut-2-yn-yl)-3-(S)-(4-fluorophenyl)morpholine;    or a pharmaceutically acceptable salt thereof.

Suitable atypical anti-depressants include: bupropion, lithium,nefazodone, trazodone and viloxazine, and pharmaceutically acceptablesalts thereof. Suitable classes of anti-anxiety agents includebenzodiazepines and 5-HT_(1A) agonists or antagonists, especially5-HT_(1A) partial agonists, and corticotropin releasing factor (CRF)antagonists.

Suitable benzodiazepines include: alprazolam, chlordiazepoxide,clonazepam, chlorazepate, diazepaam, halazepam, lorazepam, oxazepam andprazepam, and pharmaceutically acceptable salts thereof.

Suitable 5-HT_(1A) receptor agonists or antagonists include, inparticular, the 5-HT_(1A) receptor partial agonists buspirone,flesinoxan, gepirone and ipsapirone, and pharmaceutically acceptablesalts thereof.

Suitable corticotropin releasing factor (CRF) antagonists include thosepreviously discussed herein.

As used herein, the term “substance abuse disorders” includes substancedependence or abuse with or without physiological dependence. Thesubstances associated with these disorders are: alcohol, amphetamines(or amphetamine-like substances), caffeine, cannabis, cocaine,hallucinogens, inhalants, marijuana, nicotine, opioids, phencyclidine(or phencyclidine-like compounds), sedative-hypnotics orbenzodiazepines, and other (or unknown) substances and combinations ofall of the above.

In particular, the term “substance abuse disorders” includes drugwithdrawal disorders such as alcohol withdrawal with or withoutperceptual disturbances; alcohol withdrawal delirium; amphetaminewithdrawal; cocaine withdrawal; nicotine withdrawal; opioid withdrawal;sedative, hypnotic or anxiolytic withdrawal with or without perceptualdisturbances; sedative, hypnotic or anxiolytic withdrawal delirium; andwithdrawal symptoms due to other substances. It will be appreciated thatreference to treatment of nicotine withdrawal includes the treatment ofsymptoms associated with smoking cessation. Other “substance abusedisorders” include substance-induced anxiety disorder with onset duringwithdrawal; substance-induced mood disorder with onset duringwithdrawal; and substance-induced sleep disorder with onset duringwithdrawal.

It will be appreciated that a combination of a conventionalantipsychotic drug with a CB1 receptor modulator may provide an enhancedeffect in the treatment of mania. Such a combination would be expectedto provide for a rapid onset of action to treat a manic episode therebyenabling prescription on an “as needed basis”. Furthermore, such acombination may enable a lower dose of the antispychotic agent to beused without compromising the efficacy of the antipsychotic agent,thereby minimizing the risk of adverse side-effects. A yet furtheradvantage of such a combination is that, due to the action of the CB1receptor modulator, adverse side-effects caused by the antipsychoticagent such as acute dystonias, dyskinesias, akathesia and tremor may bereduced or prevented.

Thus, according to a further aspect of the present invention there isprovided the use of a CB1 receptor modulator and an antipsychotic agentfor the manufacture of a medicament for the treatment or prevention ofmania. The present invention also provides a method for the treatment orprevention of mania, which method comprises administration to a patientin need of such treatment or at risk of developing mania of an amount ofa CB1 receptor modulator and an amount of an antipsychotic agent, suchthat together they give effective relief.

In a further aspect of the present invention, there is provided apharmaceutical composition comprising a CB1 receptor modulator and anantipsychotic agent, together with at least one pharmaceuticallyacceptable carrier or excipient.

It will be appreciated that the CB1 receptor modulator and theantipsychotic agent may be present as a combined preparation forsimultaneous, separate or sequential use for the treatment or preventionof mania. Such combined preparations may be, for example, in the form ofa twin pack.

In a further or alternative aspect of the present invention, there istherefore provided a product comprising a CB1 receptor modulator and anantipsychotic agent as a combined preparation for simultaneous, separateor sequential use in the treatment or prevention of mania. It will beappreciated that when using a combination of the present invention, theCB1 receptor modulator and the antipsychotic agent may be in the samepharmaceutically acceptable carrier and therefore administeredsimultaneously. They may be in separate pharmaceutical carriers such asconventional oral dosage forms which are taken simultaneously.

The term “combination” also refers to the case where the compounds areprovided in separate dosage forms and are administered sequentially.Therefore, by way of example, the antipsychotic agent may beadministered as a tablet and then, within a reasonable period of time,the CB1 receptor modulator may be administered either as an oral dosageform such as a tablet or a fast-dissolving oral dosage form. By a“fast-dissolving oral formulation” is meant, an oral delivery form whichwhen placed on the tongue of a patient, dissolves within about 10seconds. Included within the scope of the present invention is the useof CB1 receptor modulators in combination with an antipsychotic agent inthe treatment or prevention of hypomania.

It will be appreciated that a combination of a conventionalantipsychotic drug with a CB1 receptor modulator may provide an enhancedeffect in the treatment of schizophrenic disorders. Such a combinationwould be expected to provide for a rapid onset of action to treatschizophrenic symptoms thereby enabling prescription on an “as neededbasis”. Furthermore, such a combination may enable a lower dose of theCNS agent to be used without compromising the efficacy of theantipsychotic agent, thereby minimizing the risk of adverseside-effects. A yet further advantage of such a combination is that, dueto the action of the CB1 receptor modulator, adverse side-effects causedby the antipsychotic agent such as acute dystonias, dyskinesias,akathesia and tremor may be reduced or prevented.

As used herein, the term “schizophrenic disorders” includes paranoid,disorganized, catatonic, undifferentiated and residual schizophrenia;schizophreniform disorder; schizoaffective disorder; delusionaldisorder; brief psychotic disorder; shared psychotic disorder;substance-induced psychotic disorder; and psychotic disorder nototherwise specified.

Other conditions commonly associated with schizophrenic disordersinclude self-injurious behavior (e.g. Lesch-Nyhan syndrome) and suicidalgestures.

Suitable antipsychotic agents of use in combination with a CB1 receptormodulator include the phenothiazine, thioxanthene, heterocyclicdibenzazepine, butyrophenone, diphenylbutylpiperidine and indoloneclasses of antipsychotic agent. Suitable examples of henothiazinesinclude chlorpromazine, mesoridazine, thioridazine, acetophenazine,luphenazine, perphenazine and trifluoperazine. Suitable examples ofthioxanthenes include hlorprothixene and thiothixene. Suitable examplesof dibenzazepines include clozapine and lanzapine. An example of abutyrophenone is haloperidol. An example of a diphenylbutylpiperidine ispimozide. An example of an indolone is molindolone. Other antipsychoticagents include loxapine, sulpiride and risperidone. It will beappreciated that the antipsychotic agents when used in combination witha CB1 receptor modulator may be in the form of a pharmaceuticallyacceptable salt, for example, chlorpromazine hydrochloride, mesoridazinebesylate, thioridazine hydrochloride, acetophenazine maleate,fluphenazine hydrochloride, flurphenazine enathate, fluphenazinedecanoate, trifluoperazine hydrochloride, thiothixene hydrochloride,haloperidol decanoate, loxapine succinate and molindone hydrochloride.Perphenazine, chlorprothixene, clozapine, olanzapine, haloperidol,pimozide and risperidone are commonly used in a non-salt form.

Other classes of antipsychotic agent of use in combination with a CB1receptor modulator include dopamine receptor antagonists, especially D2,D3 and D4 dopamine receptor antagonists, and muscarinic m1 receptoragonists. An example of a D3 dopamine receptor antagonist is thecompound PNU-99194A. An example of a D4 dopamine receptor antagonist isPNU-101387. An example of a muscarinic ml receptor agonist isxanomeline.

Another class of antipsychotic agent of use in combination with a CB1receptor modulator is the 5-HT_(2A) receptor antagonists, examples ofwhich include MDL100907 and fananserin. Also of use in combination witha CB1 receptor modulator are the serotonin dopamine antagonists (SDAs)which are believed to combine 5-HT2A and dopamine receptor antagonistactivity, examples of which include olanzapine and ziperasidone.

Still further, NK-1 receptor antagonists may be favorably employed withthe CB1 receptor modulators of the present invention. Preferred NK-1receptor antagonists for use in the present invention are selected fromthe classes of compounds described in European Patent Specification No.0 577 394, and International Patent Specification Nos.95/08549,95/18124, 95/23798,96/05181, and 98/49710 (Application No.PCT/GB97/01630). The preparation of such compounds is fully described inthe aforementioned publications.

Particularly preferred NK-1 receptor antagonists of use in the presentinvention include:

-   (3S,5R,6S)-3-[2-cyclopropoxy-5-(trifluoromethoxy)phenyl]-6-phenyl-1-oxa-7-aza-spiro[4.5]decane;-   (3R,5R,6S)-3-[2-cyclopropoxy-5-(trifluoromethoxy)phenyl]-6-phenyl-1-oxa-7-aza-spiro[4.5]decane;-   (+)-(2R3R,2S3S)-N-{[2-cyclopropoxy-5-(trifluoromethoxy)phenyl]methyl}-2-phenylpiperidin-3-amine;-   2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3(S)-(4-fluorophenyl)-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)morpholine;-   2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)-3-(S)-phenyl-morpholine;-   2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)-3-(S)-phenyl-morpholine;-   2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)morpholine;-   2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(5-(N,N-dimethyl-2-no)methyl-1,2,3-triazol-4-yl)methyl-3-(S)-phenylmorpholine;-   2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(5-(N,N-dimethylamino)methyl-1,2,3-triazol-4-yl)methyl-3-(S)-(4-fluorophenyl)morpholine;-   2-(R-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(4-monophosphoryl-5-oxo-1H-1,2,4-triazolo)methyl)morpholine;-   2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(1-monophosphoryl-5-oxo-1H-1,2,4-triazolo)methyl)morpholine;-   2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(2-monophosphoryl-5-oxo-1H-1,2,4-triazolo)methyl)morpholine;-   2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(5-oxyphosphoryl-1H-1,2,4-triazolo)methyl)morpholine;-   2-(S)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(1-monophosphoryl-5-oxo-4H-1,2,4-triazolo)methyl)morpholine;-   2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(4-N,N-dimethylaminobut-2-yn-yl)-3-(S)-(4-fluorophenyl)morpholine;-   2-(R)-(1-(S)-(3,5-bis(trifluoromethyl)phenyl)-2-hydroxyethoxy)-3-(S)-(4-fluorophenyl)-4-(1,2,4-triazol-3-yl)methylmorpholine    or a pharmaceutically acceptable salt thereof.

It will be appreciated that a combination of a conventionalanti-asthmatic drug with a CB1 receptor modulator may provide anenhanced effect in the treatment of asthma.

Thus, according to a further aspect of the present invention there isprovided the use of a CB1 receptor modulator and an anti-asthmatic agentfor the manufacture of a medicament for the treatment or prevention ofasthma.

The present invention also provides a method for the treatment orprevention of asthma, which method comprises administration to a patientin need of such treatment an amount of a compound of the presentinvention and an amount of an anti-asthmatic agent, such that togetherthey give effective relief.

Suitable anti-asthmatic agents of use in combination with a compound ofthe resent invention include, but are not limited to: (a) VLA-4antagonists such as natalizumab and he compounds described in U.S. Pat.No. 5,510,332, WO97/03094, WO97/02289, WO96/40781, 096/22966,WO96/20216, WO96/01644, WO96/06108, WO95/15973 and WO96/31206; (b)steroids and corticosteroids such as beclomethasone, methylprednisolone,betamethasone, prednisone, dexamethasone, and hydrocortisone; (c)antihistamines (H1-histamine antagonists) such as bromopheniramine,chlorpheniramine, dexchlorpheniramine, triprolidine, clemastine,diphenhydramine, diphenylpyraline, tripelennamine, hydroxyzine,methdilazine, promethazine, trimeprazine, azatadine, cyproheptadine,antazoline, pheniramine pyrilamine, astemizole, terfenadine, loratadine,desloratadine, cetirizine, fexofenadine, descarboethoxyloratadine, andthe like; (d) non-steroidal anti-asthmatics including β2-agonists (suchas terbutaline, metaproterenol, fenoterol, isoetharine, albuterol,bitolterol, salmeterol, epinephrine, and pirbuterol), theophylline,cromolyn sodium, atropine, ipratropium bromide, leukotriene antagonists(such as zafirlukast, montelukast, pranlukast, iralukast, pobilukast,and SKB-106,203), and leukotriene biosynthesis inhibitors (such aszileuton and BAY-1005); (e) anti-cholinergic agents including muscarinicantagonists (such as ipratropium bromide and atropine); and (f)antagonists of the chemokine receptors, especially CCR-3; andpharmaceutically acceptable salts thereof.

It will be appreciated that a combination of a conventionalanti-constipation drug with a CB1 receptor modulator may provide anenhanced effect in the treatment of constipation.

Thus, according to a further aspect of the present invention there isprovided the use of a CB1 receptor modulator and an anti-constipationagent for the manufacture of a medicament for the treatment orprevention of constipation.

The present invention also provides a method for the treatment orprevention of constipation, which method comprises administration to apatient in need of such treatment an amount of a compound of the presentinvention and an amount of an anti-constipation agent, such thattogether they give effective relief.

It will be appreciated that a combination of a conventionalanti-constipation drug with a CB1 receptor modulator may provide anenhanced effect in the treatment of chronic intestinalpseudo-obstruction.

Thus, according to a further aspect of the present invention there isprovided the use of a CB1 receptor modulator and an anti-constipationagent for the manufacture of a medicament for the treatment orprevention of chronic intestinal pseudo-obstruction.

The present invention also provides a method for the treatment orprevention of chronic intestinal pseudo-obstruction, which methodcomprises administration to a patient in need of such treatment anamount of a compound of the present invention and an amount of ananti-constipation agent, such that together they give effective relief.

Suitable anti-constipation agents of use in combination with a compoundof the present invention include, but are not limited to, osmoticagents, laxatives and detergent laxatives (or wetting agents), bulkingagents, and stimulants; and pharmaceutically acceptable salts thereof.

A particularly suitable class of osmotic agents include, but are notlimited to sorbitol, lactulose, polyethylene glycol, magnesium,phosphate, and sulfate; and pharmaceutically acceptable salts thereof. Aparticularly suitable class of laxatives and detergent laxatives,include, but are not limited to, magnesium, and docusate sodium; andpharmaceutically acceptable salts thereof.

A particularly suitable class of bulking agents include, but are notlimited to, psyllium, methylcellulose, and calcium polycarbophil; andpharmaceutically acceptable salts thereof.

A particularly suitable class of stimulants include, but are not limitedto, anthroquinones, and phenolphthalein; and pharmaceutically acceptablesalts thereof.

It will be appreciated that a combination of a conventionalanti-cirrhosis drug with a CB1 receptor modulator may provide anenhanced effect in the treatment of cirrhosis of the liver.

Thus, according to a further aspect of the present invention there isprovided the use of a CB1 receptor modulator and an anti-cirrhosis agentfor the manufacture of a medicament for the treatment or prevention ofcirrhosis of the liver.

The present invention also provides a method for the treatment orprevention of cirrhosis of the liver, which method comprisesadministration to a patient in need of such treatment an amount of acompound of the present invention and an anti-cirrhosis agent, such thattogether they give effective relief.

Suitable anti-cirrhosis agents of use in combination with a compound ofthe present invention include, but are not limited to, corticosteroids,penicillamine, colchicine, interferon-γ, 2-oxoglutarate analogs,prostaglandin analogs, and other anti-inflammatory drugs andantimetabolites such as azathioprine, methotrexate, leflunamide,indomethacin, naproxen, and 6-mercaptopurine; and pharmaceuticallyacceptable salts thereof.

The method of treatment of this invention comprises a method ofmodulating the CB1 receptor and treating CB1 receptor mediated diseasesby administering to a patient in need of such treatment a non-toxictherapeutically effective amount of a compound of this invention thatselectively antagonizes the CB1 receptor in preference to the other CBor G-protein coupled receptors.

The term “therapeutically effective amount” means the amount thecompound of structural formula I that will elicit the biological ormedical response of a tissue, system, animal or human that is beingsought by the researcher, veterinarian, medical doctor or otherclinician, which includes alleviation of the symptoms of the disorderbeing treated. The novel methods of treatment of this invention are fordisorders known to those skilled in the art. The term “mammal” includeshumans.

The weight ratio of the compound of the Formula I to the second activeingredient may be varied and will depend upon the effective dose of eachingredient. Generally, an effective dose of each will be used. Thus, forexample, when a compound of the Formula I is combined with a β-3 agonistthe weight ratio of the compound of the Formula I to the β-3 agonistwill generally range from about 1000:1 to about 1:1000, preferably about200:1 to about. 1:200. Combinations of a compound of the Formula I andother active ingredients will generally also be within theaforementioned range, but in each case, an effective dose of each activeingredient should be used.

Abbreviations used in the following Schemes and Examples:

-   Ac: acyl-   brine: saturated sodium chloride solution-   DMAP: 4-dimethylaminopyridine-   DMF: dimethylformamide-   DMSO: dimethylsulfoxide-   EDC: 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride-   Et: ethyl-   g or gm: gram-   h or hr: hours-   HOAc: acetic acid-   HOBt: 1-hydroxybenzotriazole-   HPLC: high pressure liquid chromatography-   HPLC/MS: high pressure liquid chromatography/mass spectroscopy-   in vacuo: rotoevaporation-   LC-MS or LCMS: liquid chromatography-mass spectrum-   Me: methyl-   mg: milligram-   MH: megahertz-   min: minutes-   mL: milliliter-   MPLC: medium pressure liquid chromatography-   MS or ms: mass spectrum-   N/A: Not applicable-   Ph: phenyl-   rb round bottom-   rt or RT: room temperature-   R_(t): retention time-   TFA: trifluoroacetic acid-   TBF: tetrahydrofuran-   TLC: thin layer chromatography-   uL, ul,-   μL or μl: microliter-   UV: ultra-violet

The following reaction schemes illustrate methods which may be employedfor the synthesis of the novel furo[2,3-b]pyridines of structuralformula I described in this invention. All substituents are as definedabove unless indicated otherwise. Several strategies based uponsynthetic transformations known in the literature of organic synthesismay be employed for the preparation of the title compounds of generalformula I. A preferred synthetic process which is shownretrosynthetically in reaction Scheme 1 proceeds through a suitablysubstituted 2-pyridone of general formula 2 wherein the substituentlabeled X is a functional group as described below. The 2-pyridone ofgeneral formula 2 is in turn derived from a 1,2-diarylethanone ofgeneral formula 1. Reaction Schemes 2-11 illustrate in detail thepreferred methods for the synthesis of the title compounds of generalformula I in the forward sense.

1,2-Diarylethanones of general formula 1 may be available commerciallyor they can be synthesized using one of several methods known in the artof organic synthesis. Scheme 2 illustrates two methods for the synthesisof the 1,2-diarylethanones of general formula 1. In the first example(equation 1), a substituted arylmethyl bromide of general formula 3 isconverted to a Grignard reagent with magnesium metal in a solvent suchas THF at a temperature between room temperature and the refluxingtemperature of the solvent. The resulting Grignard reagent is then addedto a substituted arylnitrile of general formula 4. Acidic hydrolysis ofthe reaction mixture followed by extraction of the organic productaffords a 1,2-diarylethanone of general formula 1 as shown. Analternative synthesis of 1,2-diarylethanones 1 which is preferred wheneither of the aryl groups Ar¹ or Ar² are optionally substituted withfunctional groups that are reactive with Grignard reagents is shown atthe bottom of reaction Scheme 2 (equation 2). Here a substitutedarylacetic acid of general formula 5 is reacted at low temperature (−78°to −50° C.) with two equivalents of a strong base such as lithiumbis(trimethylsilylamide) in an aprotic solvent such as THF. This doublydeprotonates the arylacetic acid 5 and generates a dianion whichundergoes a Dieckmann reaction when the substituted arylcarboxylateester of general formula 6 is added. In this modification of theDieckmann reaction, the intermediate D-keto acid smoothly decarboxylatesand a 1,2-diarylethanone of general formula 1 is produced.

Reaction Scheme 3 illustrates two methods for the conversion of the1,2-diarylethanone of general formula 1 into the 2-pyridones of generalformula 2 where the position-3 substituent (X in formula 2, Scheme 1) isa cyano group. This transformation is conducted using one of the twomethods illustrated in reaction Scheme 3, and the preferred methoddepends upon the selection of the substituent R³ in the resulting2-pyridone (2). When it is desired that the R³ substituent be a hydrogenatom, then the 1,2-diarylethanone of general formula 1 is firstconverted to a vinylogous amide of general formula 7 by reaction with anN,N-dimethylformamide dimethylacetal as shown in equation 1. Thecondensation reaction is conducted using the DMF acetal as the reactionsolvent at an elevated temperature, typically between room temperatureand 150° C., and the vinylogous amide 7 is produced as a mixture of Eand Z diastereoisomers. In the second step of this sequence, thevinylogous amide 7 is condensed with cyanoacetamide to afford the2-pyridone of general formula 2 (X=CN). The reaction is usuallyconducted in a polar aprotic solvent such as DMF in the presence of astrong base such as an alkali metal hydride or alkoxide.

Equation 2 at the bottom of reaction Scheme 3 illustrates an alternativeprocedure for the preparation of 2-pyridones of general formula 2 whichmay afford a superior overall yield in cases where the R³ substituent ischosen to be a group other than a hydrogen atom. In this sequence, the1,2-diarylethanone 1 is first condensed with an ortho-ester of generalformula 8 to afford vinylogous esters of general formula 9 as a mixtureof E and Z diastereoisomers. The vinylogous esters of general formula 9may then be condensed with cyanoacetamide as described above to afford2-pyridones of general formula 2.

Two methods for the final stage of the synthesis of the novel compoundsof general formula I are illustrated in reaction Schemes 4 and 5. Inreaction Scheme 4, a 2-pyridone of general formula 2 is subjected to analkylation reaction with an electrophilic reagent of general formula 10.In general formula 10, the R¹ substituent is as defined above and thegroup Y is a leaving group such as a halogen, mesylate, triflate or thelike. The alkylation of the 2-pyridone (2) is performed in a polar,aprotic solvent such as DMF using one of a variety of bases such as analkali metal carbonate or hydroxide. Deprotonation of the 2-pyridone ofgeneral formula 2 affords an ambident anion, which upon alkylationaffords a mixture of the O-alkylated product of general formula 11 andthe N-alkylated product of general formula 12. The desired product isthe O-alkylated isomer of general formula 11, which may be purified fromthe reaction mixture using standard methods such as silica gelchromatography. When the R¹ substituent is an electron-withdrawinggroup, the pKa of the methylene adjacent the R¹ substituent may besufficiently low that it is deprotonated following the alkylationreaction. In such an instance, the O-alkylated product of generalformula 11 cyclizes via an intramolecular nucleophilic attack of thedeprotonated methylene group upon the adjacent nitrile and the titlecompound of general formula I where R² is an amino group (13) isproduced. In cases where the cyclization of the O-alkylated product ofgeneral formula 11 is not spontaneous, it is first purified from thereaction mixture and then subjected to treatment with a strong base suchas lithium bis(trimethylsilylamide) in an aprotic solvent such as TBF toafford the title compounds of general formula I.

Reaction Scheme 5 illustrates an alternative method for the conversionof compounds of general formula 2 to the title compounds of generalformula I. In this sequence the 2-pyridone of general formula 2 is firstchlorinated to afford a 2-chloropyridine derivative of general formula14. The chlorination reaction can be accomplished using severalchlorination reagents. For instance, treatment of 2 with oxalyl chloridein an inert solvent such as methylene chloride produces the2-chloropyridine 14. This chlorination is typically conducted attemperatures between room temperature and the reflux temperature of thesolvent being used for periods of 1-24 hours. Alternatively, heating the2-pyridone 2 with phosphorus oxychloride in the absence of a solvent ata temperature between room temperature and 105° C. also affords the2-chloropyridine of general formula 14. The resulting 2-chloropyridine(14) is then subjected to a nucleophilic aromatic substitution reactionusing an alcohol of general formula 15 bearing the R¹ substituent andthe 2-substituted pyridine of general formula 11 is produced. Thisreaction is conducted in a suitable aprotic solvent such as toluene, DWor a halocarbon solvent and in the presence of a base such as an alkalimetal carbonate or alkoxide. While this method of converting the2-pyridone of general formula 2 to compounds of general formula 11 is atwo-step process, it has the advantage of not producing the undesiredN-alkylated product of general formula 12 which is formed in theone-step process illustrated in reaction Scheme 4.

From the discussion above it is seen that when the position-3substituent in compounds of general formula 2 is a cyano group, asillustrated in reaction Schemes 4 and 5, then the resulting substituentR² in the title compound of general formula I becomes a primary aminogroup (R²=NH₂). The primary am-ino group of compounds of general formula13 derived using these procedures may be converted to a variety ofalternative functional groups that are within the scope of thedefinition of the substituent R² defined above using methods known inthe art of organic synthesis. For instance the amino group in compoundsof general formula 13 may be converted to amides, carbamates, or ureas(16), and sulfonamides or sulfonylureas (17) by reaction with theappropriate acylating (e.g. R^(c)COCl) or sulfonylating (e.g.R^(c)SO₂Cl) reagents respectively, as outlined in reaction Scheme 6.When a compound of general formula 13 is reacted with an excess of theacylating or sulfonylating reagents shown in reaction Scheme 6, theamino group may be acylated or sulfonylated twice resulting in thecarboximide (18) or sulfonimide (19) derivatives as shown.

The primary amino group in compounds of general formula 13 may also beelaborated into other groups that are within the scope of the definitionof the substituent R² using alkylation reactions, reductive aminations,Michael additions etc. For example, alkylation of compounds of generalformula 13 using an alkylating agent of general formula 20 in thepresence of a base affords the mono- or di-alkylated derivatives ofgeneral formula 21 as shown in equation 1 of reaction Scheme 7. It isalso recognized that it is possible to employ the compounds of generalformula 13 in a sequence that combines the acylation or sulfonylationreactions shown in reaction Scheme 6 with the alkylation reactionillustrated in reaction Scheme 7. For instance when a compound ofgeneral formula 16 is subjected to the N-alkylation reaction, anN-alkylcarboxamide of general formula 23 is the product as shown inequation 2 of reaction Scheme 7. Similarly, the alkylation of a compoundof general formula 17 affords an N-alkylsulfonamide of general formula24 (eq. 3). The compounds of general formulae 16 and 17 are also usefulsubstrates for a Mitsunobu reaction sequence. Thus, the reaction ofthese compounds (16 & 17) with an alcohol of general formula 22 in thepresence of triphenylphosphine and diethyl ordiisopropylazodicarboxylate also affords the N-alkylation products 23and 24.

Finally, when a compound of general formula 16 or 17 contains a suitableleaving group or a hydroxyl group in its R^(c) substituent it ispossible to conduct either an intramolecular alkylation orintramolecular Mitsunobu reaction using the conditions described inequation 2 and 3 of reaction Scheme 7. In these cases the alkylatingreagent 20 or the alcohol 22 are omitted from the reaction mixtures anda heterocyclic compound of general formula 23 or 24 wherein thesubstituents R⁵ and R^(C) are closed to form a ring is the product.

In addition to the methods illustrated in reaction Schemes 6 and 7, theprimary amino group of compounds of general formula 13 may be furthermodified using a variety of methods known in organic synthesis. Theamino group of compounds of general formula 13 may be N-arylated usingmethods such as the copper-mediated coupling of arylboronic acids (Chan,D. M. T.; Monaco, K. L.; Wang, R.-P.; Winters, M. P. Tetrahedron Let.1998,39,2933-2936) or the palladium-mediated coupling of aryl halides(see Muci, A. R. Buchwald, S. L. Topics in Current Chemistry 2002, 219(Cross-Coupling reactions), 131-209). When the amino group of compoundsof general formula 13 is modified using one of these methods, a compoundof general formula 25 wherein R⁵ is an aromatic or heteroaromatic ringis produced as shown at the top of reaction Scheme 8. Compounds ofgeneral formula 13 may also be diazotized to afford a diazonium salt ofgeneral formula 26. Diazonium salts such as 26 may then be converted toadditional examples of compounds of general formula I wherein R² isdefined above as shown at the bottom of reaction Scheme 8. For example,the diazonium salts (26) may be utilized in Sandmeyer reactions or invarious palladium(0)-catalyzed cross coupling reactions such as Suzukicross-couplings, Heck reactions, Stille reactions and palladium-mediatedalkoxy- or aminocarbonylation reactions.

The O-alkylation/cyclization sequence for compounds of general formula 2described above is not limited to compounds where X is a cyano group asillustrated in reaction Schemes 4 and 5. The X group may be an aldehyde,ester, ketone, or any other electrophilic functional group capable ofundergoing a similar intramolecular cyclization to afford afuro[2,3-b]pyridine ring system. Two of these preferred methods for thepreparation of compounds of general formula I, employing intermediatesof general formula 2 wherein the X group is either a carboxylic ester(X=CO₂R) or a ketone (X=COR) are shown in reaction Schemes 9 and 10respectively.

Reaction Scheme 9 illustrates the synthetic process for the preparationof compounds of general formula I from an intermediate of generalformula 2 wherein X is an ester. In this process, an intermediate ofgeneral formula 27 is prepared using standard synthetic methodology. Inthis example, a compound of general formula 2 wherein the X group iscyano is first hydrolyzed to a carboxylic acid and then esterified toafford a compound of general formula 27. The hydrolysis of compound 2(X=CN) may be conducted in strong mineral acid at elevated temperatures,for instance in 50% aqueous sulfuric acid at 1500 for 6-24 hours. Thesubsequent esterification reaction may be conducted using the alcoholcomponent as the solvent with an acid catalyst at elevated temperatureor by any of the other esterification techniques known in organicsynthesis. The resulting pyridone derivative of general formula 27 isthen O-alkylated using one of the methods described in reaction Schemes4 and 5 to afford a substituted pyridine of general formula 28. Finally,the pyridine of general formula 28 is subjected to the intramolecularcyclization reaction described in reaction Schemes 4 and 5 and acompound of general formula 29 is produced. Compounds of general formula29 correspond to title compounds of general formula I where R² is ahydroxyl group, however they are also useful intermediates for thesynthesis of additional compounds of general formula I. For instancewhen it is desired to prepare compounds of general formula I wherein theR² group is defined as OR^(g), these compounds are prepared from 29using one of the methods for O-alkylation or O-arylation that are knownin organic synthesis. The hydroxyl group in compounds of general formula29 may also be converted into a leaving group such as a halide,mesylate, triflate (30) and the like. The resulting compounds (e.g. 30)bearing a leaving group at the 3-position of the furo[2,3-b]pyridine maythen be employed in a variety of nucleophilic addition-eliminationreactions or palladium(0)-catalyzed cross coupling reactions to affordadditional compounds of general formula I that are within the scope ofthis invention.

Reaction Scheme 10 illustrates the synthetic process for the preparationof compounds of general formula I from an intermediate of generalformula 2 wherein X is a ketone. In this process, an intermediate ofgeneral formula 31 is prepared using standard synthetic methodology. Forinstance, the reaction of a compound of general formula 2 wherein X is acyano group with a Grignard reagent or an organo lithium derivativeresults in the addition of the organometallic reagent to the cyanogroup. Typically this reaction is conducted using two equivalents of theorganometallic reagent. The first equivalent deprotonates the pyridoneNH group, and the second equivalent effects the nucleophilic addition tothe nitrile. Upon hydrolysis of the reaction mixture, a ketone ofgeneral formula 31 is produced. The resulting pyridone derivative ofgeneral formula 31 is then O-alkylated using one of the methodsdescribed in reaction Schemes 4 and 5 to afford a substituted pyridineof general formula 32. Finally, the pyridine of general formula 32 issubjected to the intramolecular cyclization reaction described inreaction Schemes 4 and 5 and the title compound of general formula I isproduced.

The title compounds of general formula I shown in reaction Scheme 9 mayalso be useful intermediates for further synthetic manipulation. Whenthe R² substituent of the compounds in reaction Scheme 10 is selected tobe an alkyl group, it is possible to further functionalize thissubstituent using a variety of halogenation or oxidation reactions knownin organic synthesis. In particular when the R² substituent is a methylgroup, it may be readily converted to a bromomethyl or dibromomethylgroup using N-bromosuccinimide. These intermediates may be hydrolyzed toafford compounds of general formula I wherein R² is a hydroxymethylgroup or an aldehyde respectively, and either may also be furtheroxidized to afford compounds of general formula I wherein R² is acarboxylic acid or ester. Reaction Scheme 11 illustrates one example ofthis process. A compound of general formula I (R² CH₃) is subjected tobromination with N-bromosuccinimide to afford the bromomethyl derivative33. This is then reacted with N-methylmorpholine-N-oxide (NMO) in asolvent such DMSO which in turn affords the aldehyde of general formula34. The aldehyde of general formula 34 may be converted to an ester 35directly using Corey's procedure (Corey, E. J.; Giman, N. W.; Ganem, B.E. J. Am. Chem. Soc. 1968, 90, 5616). Alternatively, aldehydes ofgeneral formula 34 may be oxidized to the carboxylic acid of generalformula 36 by a various methods such as sodium chlorite-hydrogenperoxide (Dalcanale E.; Montanari, F. J. Org. Chem. 1986, 51, 567).Finally, it is to be recognized that compounds of general formulae 34-36are also useful intermediates for the synthesis of additional titlecompounds of general formula I that are within the scope of thisinvention.

Reaction Scheme 12 illustrates an alternative method for the synthesisof compounds of general formula I which is particularly useful when theR¹ substituent is selected to be an aromatic or heteroaromaticsubstituent. In this synthetic method a pyridone of general formula 2(X=CN) is O-alkylated with an α-bromoester of general formula 37 using abase such as cesium carbonate in a solvent like DMF. The resultingsubstituted pyridine of general formula 38 is then subjected todeprotonation with a strong base such as lithiumbis(trimethylsilylamide) in an anhydrous solvent like THF. The resultingester enolate undergoes an intramolecular cyclization onto the cyanogroup and following hydrolysis of the reaction mixture, a substituted[3,2-H]furanone of general formula 39 is the product. Compounds ofgeneral formula 39 may then be converted to title compounds of generalformula I wherein R² is either a hydroxyl group (40) or a hydrogen atom(42). A β-keto ester of general formula 39 readily undergoes esterhydrolysis and decarboxylation when treated with a base such as aqueoussodium or potassium hydroxide in an alcoholic solvent at elevatedtemperatures. The resulting [3,2-R]furanone then tautomerizes to afforda 3 hydroxyfuran derivative of general formula 40. Alternatively, whenthe carbonyl group of a compound of general formula 39 is first reducedto a secondary alcohol using a reagent such as sodium borohydride inethanol and then subjected to ester hydrolysis, a β-hydroxyacid ofgeneral formula 41 is the product. A β-hydroxyester of general formula41 may then be decarboxylated and dehydrated in a single step whenheated in a basic solvent like quinoline at high temperatures(Schofield, K.; Ward, R. S.; Choudhury, A. M. J. Chem. Soc. C 1971,2834). Under these conditions, the title compound of general formula Iwherein R² is a hydrogen atom is produced. Finally it is to berecognized that compounds of general formulae 40 and 42 are also usefulintermediates for the synthesis of additional title compounds of generalformula I that are within the scope of this invention.

[3-Amino-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)furo[2,3-b]pyridin-2-yl](phenyl)methanoneStep A:3-Dimethylamino-1-(2,4-dichlorophenyl)-2-(4-chlorophenyl)prop-2-en-1-one

A solution of 4-chlorobenzyl 2,4-dichlorophenyl ketone (4.5 g, 14.4mmol) and dimethyl-formamide dimethylacetal (7.7 mL, 58 mmol) in DMF (60mL) was heated at 75° C. for 20 h. The volatiles were removed in vacuoto provide the crude product which was used directly n the next step.HPLC/MS: 354 (M+1), 356 (M+3); R_(t)=3.47 min.

Step B:6-(2,4-Dichlorophenyl)-5-(4-chlorophenyl)-2-oxo-1,2-dihydropyridine-3-nitrile

A solution of3-dimethylamino-1-(2,4-dichlorophenyl)-2-(4-chlorophenyl)prop-2-en-1-one(14.4 mmol assumed) from Step A, cyanoacetamide (1.33 g, 15.8 mmol), andmethanol (1.3 mL, 32 mmol) in DMF (35 mL) was added dropwise to asuspension of sodium hydride (60% in mineral oil) (1.45 g, 36 mmol) inDMF (16 mL) at rt. After the slow addition was complete, the reactionwas heated to 95° C. for 2.5 h. Most of the DMF was then removed invacuo before the reaction was diluted with aqueous 18% citric acidsolution. The mixture was extracted twice with methylene chloride andthe organic layers were washed with a portion of brine. The combinedorganic layers were dried over anhydrous sodium sulfate and concentratedin vacuo. The solid residue was triturated with ether, filtered, and airdried to afford the product. HPLC/MS: 375 (M+1), 377 (M+3); R_(t)=3.47min; ¹H NMR (CDCl₃): δ 6.96 (br d, J=8.4 Hz, 2H), 7.14 (d, J=8.2 Hz,1H), 7.25 (br d, J=8.4 Hz, 2H), 7.31 (dd, J=1.9 and 8.2 Hz, 1H), 7.50(d, J=2.0 Hz, 1H), 7.996 (s, 1H).

Step C:[3-Amino-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)furo[2,3-b]pyridin-2-yl](phenyl)methanone

A solution of the product from Step B (0.300 g; 0.8 mmol) in DMP (8 mL)was treated with cesium carbonate (0.521 g; 1.6 mmol),2-chloroacetophenone (0.124 g; 0.8 mmol), and stirred at roomtemperature for 16 hours. The reaction mixture was partitioned betweenethyl acetate and saturated NaHCO₃ solution. The organic layer waswashed twice with saturated NaHCO₃ solution, brine, dried (Na₂SO₄),filtered, and concentrated in vacuo. Purification by MPLC (silica gel;0% to 20% ethyl acetate:hexane gradient) afforded the title compound.HPLC/MS: 492.9 (M+1), 494.9 (M+3); R_(t)=4.58 min.

EXAMPLE 2

N-[2-Benzol-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)furo[2,3-b]pyridin-3:yl]acetamide

To a suspension of (0.020 g; 0.041 mmol) of the product of Example 1 inCH₂Cl₂ (0.5 mL) at room temperature was added acetyl chloride (3 μL;0.041 mmol), followed by a slow addition of triethylamine (5 μL; 0.041mmol). The reaction mixture was stirred at room temperature for 20minutes. The reaction was quenched with saturated NaHCO₃ solution. Thequenched reaction mixture was partitioned between ethyl acetate andsaturated NaHCO₃ solution. The organic layer was washed twice withsaturated NaHCO₃ solution, brine, dried (Na₂SO₄), filtered, andconcentrated in vacuo. Purification by MPLC (silica gel; 0% to 20% ethylacetate:hexane gradient) afforded the title compound. HPLC/MS: 534.8(M+1), 536.8 (M+3); R_(t)=4.79 min.

Using the procedure described in Example 2, the product of Example 1 wasreacted with an appropriate acid chloride to afford the followingcompounds: Exam- HPLC/MS ple Name m/z; R_(t): 3N-[5-(4-Chlorophenyl)-6-(2,4-dichlorophenyl)- 542.9 (M + 1),2-(2,2-dimethylpropanoyl)furo[2,3-b]pyridin-3- 544.8 (M + 3);yl]butanamide 5.19 min 4 N-[5-(4-Chlorophenyl)-6-(2,4-dichlorophenyl)-556.9 (M + 1), 2-(2,2-dimethylpropanoyl)furo[2,3-b]pyridin-3- 558.9 (M +3); yl]pentanamide 5.29 min

EXAMPLE 5

1-[3-Amino-5-(4-chlorophenyl-6-(2,4-dichlorophenyl)furo[2,3-b]pyridin-2-yl]ethanoneStep A:5-(4-Chlorophenyl)-6-(2,4-dichlorophenyl)-2-(2-oxopropoxy)-nicotinonitrile

A solution of 0.200 g (0.533 mmol) of the product of Step B from Example1 in DMF (4 mL) was treated with cesium carbonate (0.521 g; 1.6 mmol),chloroacetone (42 μL; 0.533 mmol), and stirred at room temperature for16 hours. The reaction mixture was partitioned between ethyl acetate andsaturated NaHCO₃ solution. The organic layer was washed twice withsaturated NaHCO₃ solution, brine, dried (Na₂SO₄), filtered, andconcentrated in vacuo. Purification by MPLC (silica gel; 0% to 20% ethylacetate-hexane gradient) gave the title compound. HPLC/MS: 430.9 (M+1),432.9 (M+3); R_(t) 4.25 min.

Step B:1-[3-Amino-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)furo[2,3-b]pyridin-2-yl]ethanone

A solution of the product from Step A (0.126 g; 0.292 mmol) in ethanol(4 mL) was treated with sodium ethoxide (0.040 g; 0.584 mmol) andstirred at reflux for 1 hour. The reaction was allowed to cool to roomtemperature and quenched with saturated NaHCO₃ solution. The reactionmixture was partitioned between ethyl acetate and saturated NaHCO₃solution. The organic layer was washed twice with saturated NaHCO₃solution, brine, dried (Na₂SO₄), filtered, and concentrated in vacuo.Purification by MPLC (silica gel; 0% to 20% ethyl acetate-hexanegradient) gave the title compound. HPLC/MS: 430.9 (M+1), 432.9 (M+3);R_(t)=4.04 min.

EXAMPLE 6

N-[2-Acetyl-5-(4-chlohophenyl)-6-(2,4-dichlorophenylfuro[2,3-b]pyridin-3:yl]acetamide

A solution of 0.040 g (0.0928 mmol) of the product of Example 5 inCH₂Cl₂ (2 mL) cooled to 0° C. was treated with acetyl chloride (7 μL;0.0928 mmol) followed by triethylamine (40 μL; 0.278 mmol). The reactionwas then allowed to warm to RT and stirred for 40 minutes. The reactionwas quenched with saturated NaHCO₃ solution. The reaction mixture waspartitioned between ethyl acetate and saturated NaHCO₃ solution. Theorganic layer was washed twice with saturated NaHCO₃ solution, brine,dried (Na₂SO₄), filtered, and concentrated in vacuo. Purification byMPLC (silica gel; 0% to 20% ethyl acetate-hexane gradient) gave thetitle compound. IPLC/MS: 472.8 (+1), 474.8 (M+3); R_(t)=4.43 min.

EXAMPLE 7

N-[2-Acetyl-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)furo[2,3-b]pyridin-3-yl]-N-(methylsulfonyl)methanesulfonamide

A solution of 0.030 g (0.0696 mmol)of the product from Example 5 inCH₂Cl₂ (1 mL) cooled to 0° C. was treated with methanesulfonyl chloride(5 μL; 0.0696 mmol), followed by triethylamine (30 μL; 0.209 mmol). Thereaction mixture was allowed to warm to room temperature and stirred for2 h. The reaction was quenched with saturated NaHCO₃ solution. Thereaction mixture was partitioned between ethyl acetate and saturatedNaHCO₃ solution. The organic layer was washed twice with saturatedNaHCO₃ solution, brine, dried (Na₂SO₄), filtered, and concentrated invacuo. Purification by MPLC (silica gel; 0% to 20% ethyl acetate:hexanegradient) gave the title compound. BPLC/MS: 586.9 (M+1), 588.9 (M+3);R_(t+)4.16 min.

EXAMPLE 8

Ethyl3-amino-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)furo[2,3-b]pyridine-2-carboxylateStep A: 2-Chloro-5-(4-chlorophenyl-6-(2,4-dichlorophenyl)nicotinonitrile

A suspension of 2.0 g (5.33 mmol) of the product of Step B from Example1 in phosphorous oxychloride (6 mL) was heated to reflux and stirred for16 h. The reaction mixture was cooled to room temperature and most ofthe excess phosphorous oxychloride was removed in vacuo. The residue wasdissolved in CH₂Cl₂ and saturated NaHCO₃ solution was added slowly toquench any remaining phosphorous oxychloride. The reaction mixture wasextracted three times with CH₂Cl₂. The combined organic extracts werewashed with saturated NaHCO₃ solution, brine, dried (Na₂SO₄), filtered,and concentrated in vacuo. Purification by MPLC (silica gel; 0% to 70%CH₂Cl₂:hexane gradient) gave the title compound. HPLC/MS: 393.0 (M+1),395.0 (M+3); R_(t)=4.48 min.

Step B: Ethyl{[5-(4-chlorophenyl)-3-cyano-6-(2,4-dichlorophenyl)pyridin-2-yl]oxy}acetate

A solution of 1.55 g (3.93 mmol) of the product from Step A in toluene(20 mL) was treated with ethyl glycolate (0.41 mL; 4.33 mmol) and cesiumcarbonate (2.54 g; 7.8 mmol). The reaction mixture was heated in asealed pressure tube at 80° C. and stirred for 6 h. The reaction mixturewas cooled to room temperature and partitioned between ethyl acetate andsaturated NaHCO₃ solution. The organic layer was washed twice withsaturated NaHCO₃ solution, brine, dried (Na₂SO₄), filtered, andconcentrated in vacuo. Purification by MPLC (silica gel; 0% to 20% ethylacetate:hexane gradient) gave the title compound. HPLC/MS: 460.9 (M+1),462.9 (M+3); R_(t)=4.50 min.

Step C: Ethyl3-amino-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)furo[2,3-b]pyridine-2-carboxylate

A solution of the product from Step B (0.130 g; 0.282 mmol) in TBF (3mL) cooled to 0° C. was treated with 1 M solution of lithiumbis(trimethylsilyl)amide in THF (0.85 mL; 0.85 mmol) and stirred at 0°C. under nitrogen for 30 minutes. The reaction mixture was quenched at0° C. with 10% aqueous NaHSO₄ solution. The reaction mixture waspartitioned between ethyl acetate and 10% NaHSO₄ aqueous solution. Theorganic layer was washed twice with saturated NaHCO₃ solution, brine,dried (Na₂SO₄), filtered, and concentrated in vacuo. Purification byMPLC (silica gel; 0% to 20% ethyl acetate:hexane gradient) gave thetitle compound. HPLC/MS: 460.9 (M+1), 462.9 (M+3); R_(t)=4.35 min.

EXAMPLES 9 & 10

Using the procedure described in Example 2, the product of Example 8 wasreacted with acetyl chloride and trifluoroacetic anhydride to afford thefollowing two compounds: HPLC/MS Example Name m/z; R_(t): 9 Ethyl3-(acetylamino)-5-(4-chlorophenyl)-6- 502.9 (M + 1),(2,4-dichlorophenyl)furo[2,3-b]pyridine-2- 504.8 (M + 3); carboxylate (R= CH₃) 4.32 min 10 Ethyl 5-(4-chlorophenyl)-6-(2,4-dichloro- 556.8 (M +1), phenyl)-3-[(trifluoroacetyl)amino]furo[2,3- 558.8(M + 3);b]pyridine-2-carboxylate 4.66 min (R = CF₃)

EXAMPLE 11

N-[5-(4-Chlorophenyl)-6-(2,4-dichlorophenyl)-2-(piperidin-1-ylcarbonyl)furo[2,3-b]pyridin-3-yl]acetamide

A solution of piperidine (10 μL; 0.119 mmol) in toluene (0.5 mL) at 0°C. was treated with 2.0 M solution of trimethylaluminum in toluene (120μL; 0.119 mmol). After the addition, the reaction mixture was warmed toroom temperature and stirred for 30 minutes. A solution of 0.030 g(0.0596 mmol) of the product from Example 9 in CH₂Cl₂ (0.5 mL) wasadded, and the reaction mixture was then stirred and heated to 60° C.for 2 hours. The reaction mixture was cooled to room temperature andquenched with 10% NaHSO₄ aqueous solution. The mixture was partitionedbetween ethyl acetate and 10% NaHSO₄ aqueous solution. The organic layerwas washed twice with saturated NaHCO₃ solution, brine, dried (Na₂SO₄),filtered, and concentrated in vacuo. Purification by MPLC (silica gel;0% to 30% ethyl acetate:hexane gradient) gave the title compound.HPLC/MS: 542.1 (M+1), 544.1 (M+3); R_(t)=4.33 min.

EXAMPLE 12

N-[5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)-2-(piperidin-1-ylcarbonyl)furo[2,3-b]pyridin-3-yl]-2,2,2-trifluoroacetamide

Using the procedure described in Example 11 above, the product ofExample 10 was converted to the title compound. BPLC/MS: 595.9 (M+1),597.9 (M+3); R_(t)=4.88 min.

EXAMPLE 13

5-(4-Chlorophenyl)-6-(2,4-dichlorophenyl)-2-(piperidin-1-ylcarbonyl)furo[2,3-b]pyridin-3-amine

A solution of 35 mg of the product of Example 12 dissolved in 1 mL ofmethanol was treated with 41 mg of K₂CO₃ at 60° C. for 2 hours. Thereaction mixture was then partitioned between EtOAc and water and theorganic product was extracted. The extracts were dried (Na₂SO₄),filtered and evaporated in vacuo to afford to afford the title compound.HPLC/MS: 500.1 (M+1), 502.1 (M+3); R_(t)=4.51 min.

EXAMPLES 14-16

The product of Example 9 was reacted with the reagents prepared fromtrimethylaluminum and either N-methylpiperazine, cyclopropylamine orpyrrolidine according to the procedure described in Example 11 to affordthe following compounds respectively: Ex- HPLC/MS ample Name m/z; R_(t):14 N-{5-(4-Chlorophenyl)-6-(2,4-dichlorophenyl)- 556.9 (M + 1),2-[(4-methylpiperazin-1-yl)carbonyl]-furo[2,3- 558.9b]pyridin-3-yl}acetamide (M + 3); 3.03 min 153-(Acetylamino)-5-(4-chlorophenyl)-N- 513.9 (M + 1),Cyclopropyl-6-(2,4-dichlorophenyl)furo[2,3- 515.9(M + 3);b]pyridine-2-carboxamide 4.16 min 16N-[5-(4-Chlorophenyl)-6-(2,4-dichlorophenyl)- 527.9 (M + 1),2-(pyrrolidin-1-ylcarbonyl)furo[2,3- 529.9 b]pyridin-3-yl]acetamide (M +3); R_(t) = 4.43 min

EXAMPLE 17

1-[3-Amino-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)furo[2,3-b]pyridin-2-yl]-2,2-dimethylpropan-1-one

A solution of 0.500 g (1.33 mmol) of the product from Step B of Example1 in DMF (13 mL) was treated with cesium carbonate (0.867 g; 2.66 mmol),1-chloropinacolone (175 μL; 1.33 mmol), and stirred at room temperaturefor 16 hours. The reaction mixture was partitioned between ethyl acetateand saturated NaHCO₃ solution. The organic layer was washed twice withsaturated NaHCO₃ solution, brine, dried (Na₂SO₄), filtered, andconcentrated in vacuo. Purification by MPLC (silica gel; 0% to 20% ethylacetate:hexane gradient) gave the title compound. HPLC/MS: 472.9 (Me⁺),474.9 (M+3); R_(t)=4.73 min.

EXAMPLE 18

N[5-(4-Chlorophenyl)-6-(2,4-dichlorophenyl)-2-(2,2-dimethylpropanoyl)furo[2,3-b]pyridin-3yl]acetamide

A solution of 0.050 g (0.106 mmol) of the product from Example 17 inCH₂Cl₂ (1 mL) at 0° C. was treated with acetyl chloride (8 μL; 0.106mmol) followed by triethylamine (15 μL; 0.106 mmol). After the addition,the reaction mixture was warmed to RT and stirred for 1 hour. Thereaction was quenched with saturated NaHCO₃ solution. The reactionmixture was partitioned between ethyl acetate and saturated NaHCO₃solution. The organic layer was washed twice with saturated NaHCO₃solution, brine, dried (Na₂SO₄), filtered, and concentrated in vacuo.Purification by MPLC (silica gel; 0% to 20% ethyl acetate-hexanegradient) gave the title compound. HPLC/MS: 515.0 (M+1), 517.0 (M+3);R_(t)=4.94 min.

Using the procedure described in Example 18, the product of Example 17was reacted with the indicated acylating reagent to afford the followingcompounds: HPLC/MS Example Name m/z; R_(t): 19N-[5-(4-Chlorophenyl)-6-(2,4-dichlorophenyl)-2-(2,2- 568.9 (M + 1),dimethylpropanoyl)furo[2,3-b]pyridin-3-yl]-2,2,2- 570.9 (M + 3);trifluoroacetamide (from 17 and trifluoroacetic anhydride) 5.24 min 20N-[5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)-2-(2,2- 545.1 (M + 1),dimethylpropanoyl)furo[2,3-b]pyridin-3-yl]-2- 547.1 (M + 3);methoxyacetamide (from 17 and methoxyacetyl chloride) 4.91 min 21N′-[5-(4-Chlorophenyl)-6-(2,4-dichlorophenyl)-2-(2,2- 544.1 (M + 1),dimethylpropanoyl)furo[2,3-b]pyridin-3-yl]-N,N- 546.1 (M + 3);dimethylurea (from 17 and dimethylcarbamoyl chloride) 4.99 min 22N-[5-(4-Chlorophenyl)-6-(2,4-dichlorophenyl)-2-(2,2- 586.2 (M + 1),dimethylpropanoyl)furo[2,3-b]pyridin-3-yl]morpholine- 588.2 (M + 3);4-carboxamide (from 17 and 4-morpholinecarbonyl 4.85 min chloride) 23N-[5-(4-Chlorophenyl)-6-(2,4-dichlorophenyl)-2-(2,2- 544.1 (M + 1),dimethylpropanoyl)furo[2,3-b]pyridin-3-yl]-N′-ethylurea 546.1 (M + 3);(from 17 and ethylisocyanate) 4.89 min 242-{[5-(4-Chlorophenyl)-6-(2,4-dichlorophenyl)-2-(2,2- 573.1 (M + 1),dimethylpropanoyl)furo[2,3-b]pyridin-3-yl]amino}-2- 575.1 (M + 3);oxoethyl acetate (from 17 and acetoxyacetyl chloride) 5.02 min

EXAMPLE 25

N-[5-(4-Chlorophenyl)-6-(2,4-dichlorophenyl)-2-(2,2-dimethylpropanoyl)furo[2,3-b]pyridin-3-yl]-2-hydroxyacetamide

To the product of Example 24 (100 mg, 0.185 mmol, dissolved in 3 mLCH₂Cl₂ and 3 mL methanol) was added Cs₂CO₃ (75 mg, 0.230 mmol). LC/MSindicated consumption of the starting material within 15 minutes, andthe reaction was quenched with 10 drops of acetic acid before dilutingwith CH₂Cl₂ and washing with saturated NaHCO₃ solution. The residue fromthe concentrated solution was purified via silica gel flashchromatography eluting with a gradient of 0 to 25% ethyl acetate/hexaneaffording 58 mg of the title compound. HPLC/MS: 531.2 (M+1), 533.1(M+3); R_(t)=1.17 min (ultrafast method).

EXAMPLE 26

[3-An-no-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)furo[2,3-b]pyridin-2-yl](pyridin-3-yl)methanone

A solution of 0.500 g (1.33 mmol) of the product from Step B of Example1 in DMP (13 mL) was treated with cesium carbonate (1.30 g; 3.99 mmol),3-(bromoacetyl)pyridine hydrobromide (0.375 g; 1.33 mmol), and stirredat room temperature for 16 hours. The reaction mixture was partitionedbetween ethyl acetate and saturated NaHCO₃ solution. The organic layerwas washed twice with saturated NaHCO₃ solution, brine, dried (Na₂SO₄),filtered, and concentrated in vacuo. Purification by MPLC (silica gel;0% to 50% ethyl acetate:hexane gradient) gave the title compound.HPLC/MS: 493.9 (M+1), 495.9 (M+3); R_(t)=3.40 min.

EXAMPLE 27

N-[5-(4-Chlorophenyl)-6-(2,4-dichlorophenyl)-2-(pyridin-3-ylcarbonyl)furo[2,3-b]pyridin-3-yl]-2,2-dimethylpropanamide

A solution of 0.200 g (0.405 mmol) of the product from Example 26 inCH₂Cl₂ (4 mL) at 0° C. was treated with trimethylacetyl chloride (50 μL;0.405 mmol) followed by triethylamine (113 μL; 0.810 mmol). After theaddition, the reaction mixture was warmed to room temperature andstirred for 16 hours. The reaction was quenched with saturated NaHCO₃solution. The reaction mixture was partitioned between ethyl acetate andsaturated NaHCO₃ solution. The organic layer was washed twice withsaturated NaHCO₃ solution, brine, dried (Na₂SO₄), filtered, andconcentrated in vacuo. Purification by MPLC (silica gel; 0% to 30% ethylacetate:hexane gradient) gave the title compound. HPLC/MS: 578.0 (M+1),580.0 (M+3); R_(t)=4.69 min.

EXAMPLE 28

Methyl5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)-2-(pyridin-3-ylcarbonyl)furo[2,3-b]pyridin-3-ylcarbamate

A solution of 0.030 g (0.0607 mmol) of the product from Example 26 inCH₂Cl₂ (0.6 mL) at 0° C. was treated with methyl chloroformate (5 μL;0.0607 mmol) followed by diisopropylethylamine (10 μL; 0.0607 mmol).After the addition, the reaction mixture was warmed to room temperatureand stirred for 16 hours. The reaction was quenched with saturatedNaHCO₃ solution. The reaction mixture was partitioned between ethylacetate and saturated NaHCO₃ solution. The organic layer was washedtwice with saturated NaHCO₃ solution, brine, dried (Na₂SO₄), filtered,and concentrated in vacuo. Purification by MPLC (silica gel; 0% to 30%ethyl acetate:hexane gradient) gave the title compound. HPLC/MS: 551.9(M+1), 553.9 (M+3); R_(t)=4.24 min.

EXAMPLE 29

N′-[5-(4-Chlorophenyl)-6-(2,4-dichlorophenyl)-2-(pyridin-3-ylcarbonyl)furo[2,3-b]pyridin-3-yl]-N,N-dimethylurea

To a suspension of sodium hydride (0.004 g; 60% dispersion; 0.111 mmol)in THF (0.5 mL) at 0° C. was added a solution of 0.050 g 0.101 mmol) ofthe product from Example 26 (in THF (0.5 mL) and the reaction mixturewas stirred at 0° C. for 30 minutes. Dimethylsulfamoyl chloride (9 μL;0.101 mmol) was added dropwise and the reaction was then stirred at roomtemperature for an additional 5 hours. The reaction was quenched withsaturated NaHCO₃ solution. The reaction mixture was partitioned betweenethyl acetate and saturated NaHCO₃ solution. The organic layer waswashed twice with saturated NaHCO₃ solution, brine, dried (Na₂SO₄),filtered, and concentrated in vacuo. Purification by MPLC (silica gel;0% to 50% ethyl acetate:hexane gradient) gave the title compound.BPLC/MS: 564.9 (M+1), 566.9 (M+3); R_(t)=4.33 min.

EXAMPLE 30

N-[5-(4-Chlorophenyl)-6-(2,4-dichlorophenyl)-2-(pyridin-3-ylcarbonyl)furo[2,3-b]pyridin-3-yl]-2,2,2-trifluoroacetamide

A solution of 0.050 g (0.101 mmol) of the product from Example 26 inCH₂Cl₂ (1 mL) at 0° C. was treated with trifluroacetic anhydride (14 μL;0.101 mmol) followed by triethylamine (15 μL; 0.111 mmol). After theaddition, the reaction mixture was warmed to room temperature andstirred for 20 minutes. The reaction was quenched with saturated NaHCO₃solution. The reaction mixture was partitioned between ethyl acetate andsaturated NaHCO₃ solution. The organic layer was washed twice withsaturated NaHCO₃ solution, brine, dried (Na₂SO₄), filtered, andconcentrated in vacuo. Purification by MPLC (silica gel; 0% to 30% ethylacetate-hexane gradient) gave the title compound. BPLC/MS: 589.9 (M+1),591.9 (M+3); R_(t)=4.64 min.

EXAMPLE 31

[3-Amino-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)furo[2,3-b]pyridin-2-yl](3,4-difluorophenyl)methanone

A solution of 0.500 g (1.33 mmol) of the product from Step B of Example1 in DMP (13 mL) was treated with cesium carbonate (0.869 g; 2.67 mmol),2-bromo-3′,4′-difluoroacetophenone (0.312 g; 1.33 mmol), and stirred atroom temperature for 16 hours. The reaction mixture was partitionedbetween ethyl acetate and saturated NaHCO₃ solution. The organic layerwas washed twice with saturated NaHCO₃ solution, brine, dried (Na₂SO₄),filtered, and concentrated in vacuo. Purification by MPLC (silica gel;0% to 20% ethyl acetate:hexane gradient) gave the title compound.HPLC/MS: 528.8 (M+1), 530.8 (M+3); R_(t) 0.76 min.

EXAMPLE 32

[3-Amino-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)furo[2,3-b]pyridin-2-yl](3,4-difluorophenyl)methanone

A solution of 0.050 g (0.0945 mmol) of the product from Example 31 inCH₂Cl₂ (1 mL) at 0° C. was treated with acetyl chloride (7 μL; 0.0945mmol) followed by diisopropylethylamine(16 μL; 0.0945 mmol). After theaddition, the reaction mixture was warmed to room temperature andstirred for 30 minutes. The reaction was quenched with saturated NaHCO₃solution. The reaction mixture was partitioned between ethyl acetate andsaturated NaHCO₃ solution. The organic layer was washed twice withsaturated NaHCO₃ solution, brine, dried (Na₂SO₄), filtered, andconcentrated in vacuo. Purification by MPLC (silica gel; 0% to 20% ethylacetate:hexane gradient) gave the title compound. HPLC/MS: 570.9 (M+1),572.9 (M+3); R_(t)=4.90 min.

EXAMPLE 33

N-[5-(4-Chlorophenyl)-6-(2,4-dichlorophenyl)-2-(2,2-dimethylpropangyl)furo[2,3-b]pyridin-3-yl]sulfamide

A solution of 0.030 g (0.0634 mmol) of the product from Example 17 inCH₂Cl₂ (0.6 mL) at 0° C. was treated with sulfamoyl chloride (7 mg;0.0634 mmol) followed by diisopropylethylamine (11 μL; 0.0634 mmol).After the addition, the reaction mixture was warmed to room temperatureand stirred for 2 hours. The reaction was quenched with saturated NaHCO₃solution. The reaction mixture was partitioned between ethyl acetate andsaturated NaHCO₃ solution. The organic layer was washed twice withsaturated NaHCO₃ solution, brine, dried (Na₂SO₄), filtered, andconcentrated in vacuo. Purification by MPLC (silica gel; 0% to 20% ethylacetate:hexane gradient) gave the title compound. HPLC/MS: 551.9 (M+1),553.9 (M+3); R_(t)=4.54 min.

EXAMPLE 34

N-[5-(4-Chlorophenyl)-6-(2,4-dichlorophenyl)-2-(2,2-dimethylpropanoyl)furo[2,3-b]pyridin-3-yl]methanesulfonamideStep A:N-[5-(4-Chlorophenyl)-6-(2,4-dichlorophenyl)-2-(2,2-dimethylpropanoyl)furo[2,3-b]pyridin-3-yl]-N-(methylsulfonyl)-methanesulfonimide

A solution of 0.030 g (0.0634 mmol) of the product from Example 17 inCH₂Cl₂ (0.6 mL) at room temperature was treated with methanesulfonylchloride (15 μL; 0.190 mmol) followed by diisopropylethylamine (33 μL;0.190 mmol). After the addition, the reaction mixture was stirred for 2hours. The reaction was quenched with saturated NaHCO₃ solution. Thereaction mixture was partitioned between ethyl acetate and saturatedNaHCO₃ solution. The organic layer was washed twice with saturatedNaHCO₃ solution, brine, dried (Na₂SO₄), filtered, and concentrated invacuo. No further purification was done, and the product was useddirectly in the next step.

Step B:N-[5-(4-Chlorophenyl)-6-(2,4-dichlorophenyl)-2-(2,2-dimethylpropanoyl)furo[2,3-b]pyridin-3-yl]methanesulfonamide

A solution of the crude product from Step A (0.0634 mmol) in methanol (1mL) was treated at room temperature with 6 N NaOH aqueous solution (50μL; 0.317 mmol) and stirred for 1 hour. The reaction mixture wasneutralized to pH=7 with 2 N HCl solution and extracted 3 times withCH₂Cl₂. The combined extracts were washed with brine, dried (Na₂SO₄),filtered, and concentrated in vacuo. Purification by MPLC (silica gel;0% to 20% ethyl acetate-hexane gradient) gave the title compound.HPLC/MS: 551.0 (M+1), 553.0 (M+3); R_(t)=4.88 min.

EXAMPLE 35

N-[2-(2-Azabicyclo[2.2.2]oct-2-ylcarbonyl)-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)furo[2,3-b]pyridin-3-yl]acetamideStep A:3-(Acetylamino)-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)furo-[2,3-b]pyridine-2-carboxylicacid

A solution of 0.035 g (0.0695 mmol) of the product from Example 9 inmethanol (0.6 mL) was treated with 3 N NaOH aqueous solution (100 μL;0.345 mmol) and stirred for 3 hours. The reaction mixture was quenchedwith 2 N HCl solution and extracted 3 times with CH₂Cl₂. The combinedextracts were washed with brine, dried (Na₂SO₄), filtered, andconcentrated in vacuo. No further purification was done and the productwas used directly in the next step.

Step B:N-[2-(2-Azabicyclo[2.2.2]oct-2-ylcarbonyl)-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)furo[2,3-b]pyridin-3-yl]acetamide

A solution of 0.027 g (0.0568 mmol) of the product from Step A in CH₂Cl₂(0.6 mL) was treated with 2-azabicyclo[2.2.2]octane hydrochloride (0.009g; 0.0625 mmol), EDC (0.016 g; 0.0852 mmol), DMAP (0.007 g; 0.0568mmol), and 1-methylmorpholine (19 μL; 0.170 mmol), then stirred at roomtemperature for 16 hours. The reaction mixture was partitioned betweenethyl acetate and saturated NaHCO₃ solution. The organic layer waswashed twice with saturated NaHCO₃ solution, brine, dried (Na₂SO₄),filtered, and concentrated in vacuo. Purification by MPLC (silica gel;0% to 20% ethyl acetate:hexane gradient) gave the title compound.BPLC/MS: 568.0 (M+1), 570.0 (M+3); R_(t)=4.68 min.

EXAMPLE 36

1-[3-Amino-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)furo[2,3-b]pyridin-2-yl]propan-1-one

A solution of 0.500 g (1.33 mmol) of the product from Step B of Example1 in DMF (13 mL) was treated with cesium carbonate (1.30 g; 3.99 mmol),1-bromo-2-butanone (136 μL; 1.33 mmol), and stirred at room temperaturefor 16 hours. The reaction mixture was partitioned between ethyl acetateand saturated NaHCO₃ solution. The organic layer was washed twice withsaturated NaHCO₃ solution, brine, dried (Na₂SO₄), filtered, andconcentrated in vacuo. Purification by MPLC (silica gel; 0% to 20% ethylacetate-hexane gradient) gave the title compound. BPLC/MS: 444.9 (M+1),446.9 (M+3); R_(t)=4.65 min.

EXAMPLE 37

1-[5-(4-Chlorophenyl)-6-(2,4-dichlorophenyl)-3-(methylamino)furo[2,3-b]pyridin-2-yl]-2,2-dimethylpropan-1-oneStep A:N-[5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)-2-(2,2-dimethylpropanoyl)furo[2,3-b]pyridin-3-yl]-2,2,2-trifluoro-N-methylacetamide

A solution of 0.040 g (0.0703 mmol) of the product from Example 19 inDMF (1 mL) cooled to 0° C. was treated with sodium hydride (0.004 g; 60%dispersion; 0.0967 mmol). The reaction mixture was stirred at 0° C. for20 minutes and then treated with iodomethane (16 μL; 0.263 mmol). Thereaction mixture was warmed to room temperature and stirred for 1 hour.The reaction was quenched with saturated NaHCO₃ solution. The reactionmixture was partitioned between ethyl acetate and saturated NaHCO₃solution. The organic layer was washed twice with saturated NaHCO₃solution, brine, dried (Na₂SO₄), filtered, and concentrated in vacuo. Nofurther purification was done, and the crude product was used directlyin the next step.

Step B:1-[5-(4-Chlorophenyl)-6-(2,4-dichlorophenyl)-3-(methylamino)furo-[2,3-b]pyridin-2-yl]-2,2-dimethylpropan-1-one

A solution of the product from Step A (0.0703 mmol) in methanol (2 mL)and water (0.1 mL) was treated with potassium carbonate (0.049 g; 0.351mmol) at room temperature. The reaction mixture was stirred a roomtemperature until the reaction was judged complete by TLC analysis. Thereaction mixture was then partitioned between ethyl acetate andsaturated NaHCO₃ solution. The organic layer was washed twice withsaturated NaHCO₃ solution, brine, dried (Na₂SO₄), filtered, andconcentrated in vacuo. Purification by MPLC (silica gel; 0% to 20% ethylacetate:hexane gradient) gave the title compound. HPLC/MS: 487.0 (M+1),489.0 (M+3); R_(t)=5.03 min.

EXAMPLE 38

1-[5-(4-Chlorophenyl)-6-(2,4-dichlorophenyl)-3-(dimethylamino)furo[2,3-b]pyridin-2-yl]-2,2-dimethylpropan-1-one

A solution of 0.050 g (0.106 mmol) of the product from Example 17 in DMF(1 mL) at 0° C. was treated with sodium hydride (0.010 g; 60%dispersion; 0.232 mmol). After the addition, the reaction mixture wasstirred for 20 minutes at 0° C., and then treated with iodomethane (26μL; 0.424 mmol). The reaction was warmed to room temperature and stirredfor 2 hours. The reaction was quenched with saturated NaHCO₃ solution.The reaction mixture was partitioned between ethyl acetate and saturatedNaHCO₃ solution. The organic layer was washed twice with saturatedNaHCO₃ solution, brine, dried (Na₂SO₄), filtered, and concentrated invacuo. Purification by MPLC (silica gel; 0% to 20% ethyl acetate:hexanegradient) gave the title compound. HPLC/MS: 501.0 (M+1), 503.0 (N+3);R_(t)=5.08 min.

EXAMPLE 39

[5-(4-Chlorophenyl)-6-(2,4-dichlorophenyl)-3-(dimethylamino)furo[2,3-b]pyridin-2-yl](pyridin-3-yl)methanone

A solution of 0.050 g (0.101 mmol) of the product from Example 26 in DMF(1 mL) at 0° C. was treated with sodium hydride (0.008 g; 60%dispersion; 0.213 mmol). After the addition, the reaction mixture wasstirred for 20 minutes at 0° C., and then treated with iodomethane (19μL; 0.303 mmol). The reaction was warmed to room temperature and stirredfor 1 h. The reaction was quenched with saturated NaHCO₃ solution. Thereaction mixture was partitioned between ethyl acetate and saturatedNaHCO₃ solution. The organic layer was washed twice with saturatedNaHCO₃ solution, brine, dried (Na₂SO₄), filtered, and concentrated invacuo. Purification by MPLC (silica gel; 0% to 50% ethyl acetate-hexanegradient) gave the title compound. HPLC/MS: 521.9 (M+1), 523.9 (M+3);R_(t)=3.96 min.

EXAMPLE 40

1-[5-(4-Chlorophenyl)-6-(2,4-dichlorophenyl)-3-(ethylamino)furo[2,3-b]pyridin-2-yl]-2,2-dimethylpropan-1-one

Using the procedure described in Example 39, the product of Example 17was reacted with one equivalent of ethyl bromide to afford the titlecompound. HPLC/MS: 500.9 (M+1), 502.9 (M+3); R_(t)=4.08 min.

EXAMPLE 41

3-Amino-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)furo[2,3-b]pyridine-2-carbonitrileStep A:5-(4-Chlorophenyl)-2-(cyanomethoxy)-6-(2,4-dichlorophenyl)-nicotinonitrile

A solution of 0.250 g (0.667 mmol) of the product from Step B of Example1 in DMF (7 mL) was treated with cesium carbonate (0.652 g; 2.00 mmol),and bromoacetonitrile (50 μL; 0.667; mmol), then stirred at roomtemperature for 16 h. The reaction mixture was partitioned between ethylacetate and saturated NaHCO₃ solution. The organic layer was washedtwice with saturated NaHCO₃ solution, brine, dried (Na₂SO₄), filtered,and concentrated in vacuo. Purification by MPLC (silica gel; 0% to 30%ethyl acetate-hexane gradient) gave the title compound. HPLC/MS: 413.9(N+1), 415.9 (M+3); R_(t)=4.54 min.

Step B:3-Amino-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)furo[2,3-b]-pyridine-2-carbonitrile

A solution of the product from Step A (0.132 g; 0.319 mmol) in TB (3 mL)cooled to 0° C. was treated with 1 M solution of lithiumbis(trimethylsilyl)amide in THF (701 μL; 0.701 mmol) and stirred at 0°C. under nitrogen for 15 minutes. The reaction mixture was warmed toroom temperature and then stirred for an additional 15 minutes. Thereaction mixture was partitioned between EtOAc and 10% NaHSO₄ aqueoussolution. The organic layer was washed twice with saturated NaHCO₃solution, brine, dried (Na₂SO₄), filtered, and concentrated in vacuo.Purification by MPLC (silica gel; 0% to 30% ethyl acetate-hexanegradient) gave the title compound. HPLC/MS: 413.9 (M+1), 415.9 (M+3);R_(t)=4.50 min.

EXAMPLE 42

1-[3-Amino-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)furo[2,3-b]pyridin-2-yl]-2-methylpropan-1-oneStep A: 1-Diazo-3-methylbutan-2-one

To a solution of 0.976 g (0.96 mL, 9.2 mmol) of isobutyryl chloride in18 mL ether was added 46 mL of a 0.5 M solution of diazomethane in ether(23 mmol), and the reaction mixture was stirred at 0° C. for 3 h. Thevolatiles were then removed in vacuo and the residual yellow oil wasused directly in the next step.

Step B: 1-Chloro-3-methylbutan-2-one

To a solution of 0.040 g (0.36 mmol) of the product of Step A in 2 mLether was added 0.45 mL of a 4 N solution of hydrochloric acid indioxane at 0° C. Nitrogen was evolved and the reaction mixture wasstirred for 45 min and allowed to warm to room temperature. Thevolatiles were removed in vacuo and the residual chloroketone was useddirectly in the next step.

Step C:1-[3-Amino-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)furo[2,3-b]-pyridin-2-yl]-2-methylpropan-1-one

To the product of Step B dissolved in 2 mL of anhydrous DMF was added0.134 g (0.36 mmol) of the product of Step B in Example 1 followed by0.349 g (3 equivalents) of cesium carbonate, and the reaction mixturewas stirred at from temperature for 45 min. An addition 0.100 g ofcesium carbonate was then added and the reaction mixture was stirred andheated at 60° C. for 45 min. The reaction mixture was cooled to roomtemperature and partitioned between EtOAc and saturated NaHCO₃. Theorganic layer was separated, washed with aq. NaHCO₃, brine, dried(Na₂SO₄), filtered and evaporated. The residue was purified on a silicagel flash chromatography column eluted with 0-20% EtOAc-hexane.Evaporation of the purified fractions and drying in vacuo afforded thetitle compound. HPLC/MS: 459.1 (M+1), 461.1 (M+3); R_(t)=4.51 min.

Using the procedures described in Steps A and B of Example 42,cyclopropylcarbonyl chloride and cyclobutylcarbonyl chloride werehomologated to the corresponding α-chloroketones. These were in turnused in the procedure described in Step C of Example 42 to afford thefollowing compounds respectively: HPLC/MS Example Name m/z; R_(t): 43[3-Amino-5-(4-chlorophenyl)-6-(2,4- 457.0 (M + 1),dichlorophenyl)furo[2,3-b]pyridin-2- 459.0 (M + 3);yl](cyclopropyl)methanone 4.52 min 44[3-Amino-5-(4-chlorophenyl)-6-(2,4- 471.1 (M + 1),dichlorophenyl)furo[2,3-b]pyridin-2- 473.1 (M + 3);yl](cyclobutyl)methanone 4.66 min

EXAMPLES 45 & 46

Using the general acylation procedure described in Example 18, theproducts of 10 Examples 43 and 44 were reacted with acetoxyacetylchloride to afford the corresponding acetoxyacetamides. These compoundswere in turn subjected to the general hydrolysis procedure described inExample 25 to afford the following compounds: Ex- HPLC/MS ample Namem/z; R_(t): 45 N-[5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)- 516.9 (M +1), 2-isobutyrylfuro[2,3-b]pyridin-3- 518.9 (M + 3);yl]-2-hydroxyacetamide 4.43 min 46N-[5-(4-chlorophenyl)-2-(cyclobutylcarbonyl)- 529.0 (M + 1),6-(2,4-dichlorophenyl)furo[2,3-b]pyridin- 531.0 (M + 3);3-yl]-2-hydroxyacetamide 4.59 min

EXAMPLE 47

4-Chloro-N-[5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)-2-(2,2-dimethylpropanoyl)furo[2,3-b]pyridin-3-yl]butanamide

To a magnetically stirred solution of 0.300 g (0.63 mmol) of the productof Example 17 in 6 mL of CH₂Cl₂ at 0° C. was added 70 μL (0.63 mmol) of4-chlorobutyryl chloride and 96 mg (0.95 mmol) of triethylamine. Thereaction was stirred for 1.5 h and allowed to warm to room temperature.The reaction mixture was then partitioned between saturated aqueousNaHCO₃ and EtOAc. The organic layer was separated, washed with aq.NaHCO₃, brine, then dried (Na₂SO₄), filtered and evaporated. The residuewas purified on a silica gel flash chromatography column eluted with0-20% EtOAc-hexane. Evaporation of the purified fractions and drying invacuo afforded the title compound. HPLC/MS: 577.0 (M+1), 578.9 (M+3);R_(t)=5.05 min.

EXAMPLE 48

1-[5-(4-Chlorophenyl)-6-(2,4-dichlorophenyl)-2-(2,2-dimethylpropanoyl)furo[2,3-b]pyridin-3-yl]pyrrolidin-2-one

To a magnetically stirred suspension of 7 mg (0.173 mmol) of sodiumhydride in 1 mL THF was slowly added 0.100 g (0.173 mmol) of the productof Example 47 dissolved in 1 mL of THF. After 15 min the addition wascomplete and the reaction mixture was stirred and heated to 60° C. for3.5 h. The reaction was then cooled to room temperature, and partitionedbetween saturated aq. NaHCO₃ and EtOAc. The organic product wasextracted into EtOAc, separated, dried (Na₂SO₄) filtered and evaporated.The residue was purified on a silica gel flash chromatography columneluted with 0-20% EtOAc-hexane. Evaporation of the purified fractionsand drying in vacuo afforded the title compound. HPLC/MS: 541.0 (M+1),542.9 (M+3); R_(t)=4.60 min.

EXAMPLE 49

N-[5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)-2-(2-hydroxy-2-methylpropanoyl)furo[2,3-b]pyridin-3-yl]-2-hydroxyacetamideStep A: 1-Bromo-3-hydroxy-3-methylbutan-2-one

3-Hydroxy-3-methyl-2-butanone (12.0 g), bromine (18.78 g) and ethylether (100 mL) were combined at room temperature. After a few minutes astrong exotherm began which necessitated ice/water cooling and thereaction color changed from dark red to light orange. The reactionmixture was concentrated and redissolved in ethyl ether 4 times to givethe titled compound.

Step B:1-[3-amino-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)furo[2,3-b]pyridin-2-yl]-2-hydroxy-2-methylpropan-1-one

The crude bromoketone (8.0 mmol) from Step A and the pyridone (1.0 g;2.67 mmol) from Step B of Example 1, cesium carbonate (1.74 g, 5.34mmol) and DMF (15 mL) were combined and stirred at room temperature for1 h then an additional 0.870 g of cesium carbonate was added and thereaction mixture was heated to 60° C. After 1 h at 60° C. the reactionmixture was allowed to cool to room temperature. The reaction mixturewas diluted with ethyl acetate, and washed with water, and brine. Thesolution was dried and concentrated. The residue was purified on asilica gel MPLC system eluted with a solvent gradient of 0 to 60% ethylacetate/hexanes. Evaporation of the purified fractions and drying invacuo afforded the title compound. BPLC/MS 476.8 (M+2); R_(t)=4.18 min.

Step C:2-{[5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)-2-(2-hydroxy-2-methylpropanoyl)furo[2,3-b]pyridin-3-yl]amino}-2-oxoethylacetate

The product of Step B (0.120 g; 0.253 mmol) and acetoxyacetyl chloride(0.11 mL; 1.01 mmol) were added to 2 mL of acetonitrile and stirred atroom temperature. After 50 minutes the reaction mixture was diluted withethyl acetate and washed two times with aqueous sodium bicarbonate. Theorganic layer was dried over sodium sulfate then concentrated. Theresidue was triturated in 10 mL of methanol. The solid product wascollected and rinsed two times with methanol then dried in vacuo.HPLC/MS 576.8 (M+2); R_(t)=4.32 min.

Step D:N-[5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)-2-(2-hydroxy-2-methylpropanoyl)furo[2,3-b]pyridin-3-yl]-2-hydroxyacetamide

Lithium hydroxide-H₂O (0.004 g; 0.174 mmol), the product of Step C(0.100 g; 0.174 mmol), and methanol (0.3 mL) were combined in 2 mL ofTHF and stirred at room temperature. The reaction was monitored by TLCuntil complete at which point the reaction was quenched by addition of0.50 mL of acetic acid. The reaction was diluted with ethyl acetate andthen washed two times with aqueous sodium bicarbonate. The solution wasconcentrated and purified via MPLC chromatography on silica gel with agradient elution of 0 to 50% ethyl acetate/hexanes. The product wasfurther purified by recrystallization from ethanol to afford the titlecompound. HPLC/MS 534.8 (M+2); R_(t)=4.09 min.

EXAMPLE 50

5-(4-Chlorophenyl)-6-(2,4-dichlorophenyl)-2-(3,4-difluorophenyl)furo[2,3-b]pyridin-3-olStep A: Methyl{[5-(4-chlorophenyl)-3-cyano-6-(2,4-dichlorophenyl)pyridin-2-yl]oxy}(3,4-difluorophenyl)acetate

To a magnetically stirred solution of 1.78 g (4.7 mmol) of the productof Step B in Example 1 dissolved in 10 mL DMP was added 1.25 g (4.7mmol) of methyl o-bromo-3,4difluorophenylacetate and 1.68 g (5.17 mmol)of cesium carbonate, and the reaction mixture was stirred for 2 h atroom temperature. The reaction mixture was then partitioned betweenEtOAc and water and the organic product was separated. The organicextracts were washed with water, dried (MgSO₄), filtered and evaporated.The residue was then purified on a silica gel flash chromatographycolumn eluted with 0-20% EtOAc-hexane. The purified fractions werecombined and evaporated in vacuo to afford the title compound.

Step B: Methyl5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)-2-(3,4-difluorophenyl)-3-oxo-2,3-dihydrofuro[2,3-b]pyridine-2-carboxylate

To a magnetically stirred solution of 1.20 g (2.14 mmol) the product ofStep A dissolved in 12 mL of THF was slowly added 3.2 mL of a 1.0 Nsolution (3.2 mmol) of lithium bis(trimethylsilylamide) in THF at 0° C.The reaction mixture was stirred for 30 min and allowed to warm to roomtemperature. The reaction mixture was then quenched by addition ofexcesss 10% aqueous NaHSO₄ and extracted into EtOAc. The organic layerwas separated, washed with water, dried (MgSO₄), filtered andevaporated. The residue was purified on a silica gel flashchromatography column eluted with chloroform. Combination of thepurified fractions and drying in vacuo afforded the title compound.

Step C:5-(4-Chlorophenyl)-6-(2,4-dichlorophenyl)-2-(3,4-difluorophenyl)-furo[2,3-b]pyridin-3-ol

To a solution of 80 mg (0.14 mmol) of the product of Step B dissolved in1 mL EtOH was added 9 mg (0.20 mmol) of sodium borohydride. The reactionmixture was stirred at RT for 5 min then partitioned between EtOAc andwater. The organic layer was separated, dried (MgSO₄), filtered andevaporated. The residue was then redissolved in 10 mL MeOH and 2 mL of a2.0 N solution of sodium hydroxide was added. The reaction mixture wasstirred at 80° C. for 0.5 h, then cooled to room temperature andpartitioned between EtOAc and 10% aq. NaHSO₄. The organic layer wasseparated, washed with water, dried (MgSO₄), filtered and evaporated.The residue was purified on a silica gel flash chromatography columneluted with 0-20% EtOAc-hexane. Combination of the purified fractionsand drying in vacuo afforded the title compound.

EXAMPLE 51

1-[3-An-ino-6-(2-chlorophenyl)-5-(4-chlorophenyl)furo[2,3-b]pyridin-2-yl]-2,2-dimethylpropan-1-oneStep A:1-(2-Chlorophenyl)-2-(4-chlorophenyl)-3-(dimethylamino)prop-2-en-1-one

To 13.2 g of 1-(2-chlorophenyl)-2-(4-chlorophenyl)ethanone in 100 mL ofDMF was added 23.8 g of N,N-dimethylormamide dimethyl acetal. Themixture was stirred at 75° C. for 16 hours. The solution was thenconcentrated and used without further purification in the next step.

Step B:6-(2-Chlorophenyl)-5-(4-chlorophenyl)-2-oxo-1,2-dihydropyridine-3-carbonitrile

A solution of the crude product from step A dissolved in 80 mL of DMFcontaining 4.4 mL methanol and 4.61 g cyanoacetamide was transferred bycannula into a flask containing a suspension of NaH (4.98 g, 60%dispersion in mineral oil, freed of excess oil by washing with hexanejust prior to use) in DMF (40 mL). The solution was heated to 95° C. for2.5 hours then concentrated. The residue was dissolved in ethyl acetate,washed twice with 10% aqueous NaHSO₄, and twice with water beforeconcentrating to a solid. The solid was suspended in warm ethanol andthen cooled, and the title compound was subsequently isolated byfiltration and dried in vacuo.

Step C:1-[3-Amino-6-(2-chlorophenyl)-5-(4-chlorophenyl)furo[2,3-b]pyridin-2-yl]-2,2-dimethylpropan-1-one

To a solution of 0.5 g (1.46 mmol) of the product of Step B in 10 mL DMFwas added 0.954 g Cs₂CO₃ and 0.197 mL of 1-bromopinacolone. The reactionwas stirred 17 hours at room temperature at which point the reactionmixture was diluted with ethyl acetate and washed with saturatedNaCl/NaHCO₃ solution (1:1). The residue from the concentrated solutionwas purified via silica gel flash chromatography eluting with a gradientof 0 to 75% ethyl acetate/hexane to afford the title compound. BPLC-MS:439.1 (M+1), 441.1 (M+3); R_(t)=4.53 min.

EXAMPLES 52-73

Using procedures similar to that described in Example 18, the product ofExample 51 was reacted with the indicated reagents to afford thefollowing compounds: HPLC/MS Example Name m/z; Rt: 52N-[6-(2-Chlorophenyl)-5-(4-Chlorophenyl)-2-(2,2- 481.0 (M + 1),dimethylpropanoyl)furo[2,3-b]pyridin-3-yl]acetamide 483.0 (M + 3); (fromacetyl chloride) 4.66 min 53N-[6-(2-Chlorophenyl)-5-(4-chlorophenyl)-2-(2,2- 511.4 (M + 1),dimethylpropanoyl)furo[2,3-b]pyridin-3-yl]-2- 513.1 (M + 3);methoxyacetamide (from methoxyacetyl chloride) 4.83 min 542-{[6-(2-Chlorophenyl)-5-(4-chlorophenyl)-2-(2,2- 539.2 (M + 1),dimethylpropanoyl)furo[2,3-b]pyridin-3-yl]amino}-2- 541.2 (M + 3);oxoethyl acetate (from acetoxyacetyl chloride) 4.80 min 55N′-[6-(2-Chlorophenyl)-5-(4-chlorophenyl)-2-(2,2- 510.1 (M + 1),dimethylpropanoyl)furo[2,3-b]pyridin-3-yl]-N,N- 512.1 (M + 3);dimethylurea (from dimethylcarbamoyl chloride) 4.75 min 56N-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2,2- 517.1 (M + 1),dimethylpropanoyl)furo[2,3-b]pyridin-3- 519.1 (M + 3);yl]methanesulfonamide (from methanesulfonyl chloride) 4.45 min 57N-[6-(2-Chlorophenyl)-5-(4-chlorophenyl)-2-(2,2- 552.2 (M + 1),dimethylpropanoyl)furo[2,3-b]pyridin-3- 554.2 (M + 3);yl]morpholine-4-carboxamide (from 4-morpholinecarbonyl 4.97 minchloride) 58 2-Chloro-N-[6-(2-chlorophenyl)-5-(4-chlorophenyl)- 515.1(M + 1), 2-(2,2-dimethylpropanoyl)furo[2,3-b]pyridin-3- 517.1 (M + 3);yl]acetamide (from chloroacetyl chloride) 4.70 min 59(1S)-2-{[6-(2-Chlorophenyl)-5-(4-chlorophenyl)-2- 553.0 (M + 1),(2,2-dimethylpropanoyl)furo[2,3-b]pyridin-3- 555.0 (M + 3);yl]amino}-1-methyl-2-oxoethyl acetate (from (S)-(−)- 4.78 min2-acetoxypropionyl chloride) 60 Ethyl[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2,2- 510.9 (M + 1),dimethylpropanoyl)furo[2,3-b]pyridin-3-yl]carbamate 512.9 (M + 3); (fromethyl chloroformate) 4.98 min 61 Ethyl{[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2,2- 538.9 (M + 1),dimethylpropanoyl)furo[2,3-b]pyridin-3- 540.8 (M + 3);yl]amino}(oxo)acetate (from ethyl oxalyl chloride) 4.74 min 62N-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2,2- 632.1 (M + 1),dimethyl-propanoyl)furo[2,3-b]pyridin-3-yl]-1- 634.0 (M + 3);(trifluoroacetyl)-(S)-prolinamide (from (S)-(−)-N- 4.66 min(trifluoroacetyl)prolyl chloride) 633-chloro-N-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2- 579.0 (M + 1),(2,2-dimethylpropanoyl)furo[2,3-b]pyridin-3- 581.0 (M + 3);yl]propane-1-sulfonamide (from 3- 4.61 min chloropropanesulfonylchloride) 64 1-[6-(2-Chlorophenyl)-5-(4-chlorophenyl)-3- 467.1 (M + 1),(dimethylamino)furo[2,3-b]pyridin-2-yl]-2,2- 469.1 (M + 3);dimethylpropan-1-one (methyl iodide) 4.67 min 651-[6-(2-Chlorophenyl)-5-(4-chlorophenyl)-3- 467.1 (M + 1),(ethylamino)furo[2,3-b]pyridin-2-yl]-2,2- 469.1 (M + 3);dimethylpropan-1-one (from ethyl bromide) 4.77 min 66N′-[6-(2-Chlorophenyl)-5-(4-chlorophenyl)-2-(2,2- 494.0 (M + 1),dimethylpropanoyl)furo[2,3-b]pyridin-3-yl]-N,N- 495.8 (M + 3);dimethylimidoformamide (from dimethylformamide 3.42 min dimethylacetal)67 N-[6-(2-Chlorophenyl)-5-(4-chlorophenyl)-2-(2,2- 522.9 (M + 1),dimethylpropanoyl)furo[2,3-b]pyridin-3-yl]acetamide 524.8 (M + 3); (from2 eq. acetic anhydride) 4.37 min 68 Tert-butyl[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2- 539.0 (M + 1),(2,2-dimethylpropanoyl)furo[2,3-b]pyridin-3- 540.9 (M + 3); yl]carbamate(from di-t-butyl dicarbonate) 5.25 min 691-[6-(2-Chlorophenyl)-5-(4-chlorophenyl)-2-(2,2- 521.0 (M + 1),dimethylpropanoyl)furo[2,3-b]pyridin-3- 523.0 (M + 3);yl]pyrrolidine-2,5-dione (from succinic anhydride) 4.21 min 704-[6-(2-Chlorophenyl)-5-(4-chlorophenyl)-2-(2,2- 537.0 (M + 1),dimethylpropanoyl)furo[2,3-b]pyridin-3- 539.0 (M + 3);yl]morpholine-3,5-dione (from diglycolic anhydride) 4.28 min 713-[6-(2-Chlorophenyl)-5-(4-chlorophenyl)-2-(2,2- 533.1 (M + 1),dimethylpropanoyl)furo[2,3-b]pyridin-3-yl]-3- 535.1 (M + 3);azabicyclo[3.1.0]hexane-2,4-dione (from 3- 4.31 minoxabicyclo[3.1.0]hexane-2,4-dione) 72(3S)-1-[6-(2-Chlorophenyl)-5-(4-chlorophenyl)-2- 537.1 (M + 1),(2,2-dimethylpropanoyl)furo[2,3-b]pyridin-3-yl]-3- 539.1 (M + 3);hydroxypyrrolidine-2,5-dione (from (S)-(−)-2- 4.01 min acetoxysuccinicanhydride followed by hydrolysis) 73N-[6-(2-Chlorophenyl)-5-(4-chlorophenyl)-2-(2,2- 495.1 (M + 1),dimethylpropanoyl)furo[2,3-b]pyridin-3-yl]-N- 497.0 (M + 3);methylacetamide (from acetyl chloride and methyl 4.26 min iodide)

EXAMPLE 74

N-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2,2-dimethylpropanoyl)furo[2,3-b]-pyridin-3-yl]-2-hydroxyacetamide

Using the hydrolysis procedure described in Example 25, the product ofExample 54 was converted to the title compound. BPLC-MS: 497.0 (M+1),499.0 (M+3); R_(t)=4.36 min.

N¹-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2,2-dimethylpropanoyl)furo[2,3-b]pyridin-3-yl]glycinamide

To the product of Example 58 (0.065 g, 0.126 mmol) in 2 mL DMF was added0.5 mL of a 7 M solution of NH₃ in methanol and 15 mg of KI. After 4hours the reaction was diluted with ethyl acetate and washed withsaturated NaCl/NaHCO₃ solution (1:1). The residue from the concentratedsolution was purified via silica gel preparative thin layerchromatography eluting with a 100% ethyl acetate to afford the titlecompound. HPLC-MS: 496.1 (M+1), 498.1 (M+3); R_(t)=3.46 min.

EXAMPLES 76-77

Using procedures similar to that described in Example 75, the product ofExample 58 was reacted with methylamine in THF and dimethylamine in THFto afford the following compounds respectively: Ex- HPLC/MS ample Namem/z; R_(t): 76 N¹-[6-(2-Chlorophenyl)-5-(4-chlorophenyl)-2- 510.2 (M +1), (2,2-dimethylpropanoyl)furo[2,3-b]pyridin-3- 512.2 (M + 3);yl]-N²-methylglycinamide (R¹ = H, R² = CH₃) 3.49 min 77N¹-[6-(2-Chlorophenyl)-5-(4-chlorophenyl)-2- 524.0 (M + 1),(2,2-dimethylpropanoyl)furo[2,3-b]pyridin-3- 526.0 (M + 3);yl]-N²,N²-dimethylglycinamide (R¹, R² = CH₃) 3.39 min

EXAMPLE 78

(2S)-N-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2,2-dimethylpropanoyl)furo[2,3-b]pyridin-3-yl]-2-hydroxypropanamide

Using the hydrolysis procedure described in Example 25, the product ofExample 59 was converted to the title compound. HPLC-MS: 511.0 (M+1),513.0 (M+3); R_(t)=4.47 min.

EXAMPLES 79-80

Ethylallyl[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2,2-dimethylpropanoyl)furo[2,3-b]pyridin-3-yl]carbamate(R=allyl)

To a magnetically stirred solution of 52 mg (0.125 mmol) of the productof Example 60, 7.3 mg (0.125 mmol) allyl alcohol and 33.2 mg (0.125mmol) triphenylphosphine in 1.0 mL THF was added 26 μL (0.125 mmol) ofdiisopropylazodicarboxylate at 0° C. The reaction mixture was allowed towarm to room temperature and was stirred overnight. The reaction mixturewas then concentrated in vacuo and purified on a silica gel flashchromatography column eluted with 5% EtOAc in hexane. Evaporation of thepurified fractions afforded the title compound. HPLC-MS: 551.0 (M+1),552.9 M+3); R_(t)=4.71 min.

Ethyl[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2,2-dimethylpropanoyl)furo[2,3-b]pyridin-3-yl][2-(dimethylaminoethyl]carbamate(R=N,N-dimethylaminoethyl)

Using the procedure described in the preceding example, the product ofExample 60 was subjected to Mitsunobu alkylation usingN,N-dimethylaminoethanol to afford the title compound. HPLC-MS: 582.0(M+1), 584.0 (M+3); R_(t)=3.59 min.

EXAMPLES 80-81

1-[3-(Allylamino)-6-(2-chlorophenyl)-5-(4-chlorophenyl)furo[2,3-b]pyridin-2-yl]-2,2-dimethylpropan-1-one(R=allyl)

To a stirred solution of 60 mg of the product of Example 79 in 0.5 mLmethanol and 0.22 mL of a 1.0 N aqueous sodium hydroxide solution wasadded. The reaction mixture was diluted with 5 mL THF, then stirred at80° C. overnight. The reaction was then cooled to room temperature,diluted with EtOAc, washed with water and brine, then dried (MgSO₄),filtered and evaporated. The residue was purified on a silica gel flashchromatography column eluted with 0-10% EtOAc-hexane. Evaporation of thepurified fractions afforded the title compound. BPLC-MS: 479.0 (M+1),481.0 (M+3); R_(t)=4.78 min.

1-(6-(2-Chlorophenyl)-5-(4-chlorophenyl)-3-{[2-(dimethylamino)ethyl]amino}-furo[2,3-b]pyridin-2-yl)-2,2-dimethylpropan-1-one(R=N,N-dimethylaminoethyl)

Using the procedure described in the preceding example, the product ofExample 80 was hydrolyzed to afford the title compound. HPLC-MS: 510.0(M+1), 511.9 (M+3); R_(t)=3.46 min.

EXAMPLE 82

N-[6-(2-Chlorophenyl)-5-(4-chlorophenyl)-2-(2,2-dimethylpropanoyl)furo[2,3-b]pyridin-3-yl]-L-prolinamide

To a solution of 26 mg (0.04 mmol) of the product of Example 62dissolved in 1.0 mL of CH₂Cl₂ was added a suspension of 1 mg Cs₂CO₃ in0.1 mL MeOH. The reaction was stirred at room temperature for 2 h, thenconcentrated, redissolved in CH₂Cl₂ and filtered. The filtrate wasevaporated and dried in vacuo to afford the title compound. BPLC-MS:536.1 (M+1), 538.0 (M+3); R_(t)=3.46 min.

EXAMPLE 83

1-[6-(2-Chlorophenyl)-5-(4-chlorophenyl)-3-(1,1-dioxidoisothiazolidin-2-yl)furo[2,3-b]pyridin-2-yl]-2,2-dimethylpropan-1-one

To a solution of 88 mg (0.15 mmol) of the product of Example 63dissolved in 2 mL DMF was added 6 mg of a 60% oil dispersion of sodiumhydride and the reaction mixture was stirred at 60° C. for 2 h. Thereaction mixture was then cooled to room temperature and partitionedbetween EtOAc and 10% aq. NaHSO₄. The organic layer was separated,washed with brine, dried (MgSO₄), filtered and evaporated. The residuewas purified on a silica gel flash chromatography column eluted with0-20% EtOAc-hexane. Evaporation of the purified fractions and drying invacuo afforded the title compound. HPLC-MS: 543.2 (M+1), 545.1 (M+3);R_(t)=4.29 min.

EXAMPLE 84

1-[6-(2-Chlorophenyl)-5-(4-chlorophenyl)-2-(2,2-dimethylpropanoyl)furo[2,3-b]pyridin-3-yl]-3-methylimidazolidin-2-oneStep A:N-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2,2-dimethylpropanoyl)-furo[2,3-b]pyridin-3-yl]-N-(2-hydroxyethyl)-N-methylurea

To a solution of 0.220 g (0.5 mmol) of the product of Step B in Example51 dissolved in 1 mL CH₂Cl₂ was added 0.5 mL (1.0 mmol) of 20 wt %solution of phosgene in toluene and the reaction mixture was stirred atroom temperature. After 30 min, 246 μL (3.0 mmol) of2-(methylamino)ethanol was added. Stirring was continued for 1 h andthen the reaction mixture was partitioned between CH₂Cl₂ and water. Theorganic layer was separated, washed with water, dried (Na₂SO₄), filteredand evaporated. The residue was purified on a silica gel flashchromatography column eluted with 0-40% EtOAc-hexane. Evaporation of thepurified fractions and drying in vacuo afforded the title compound.

Step B:1-[6-(2-Chlorophenyl)-5-(4-chlorophenyl)-2-(2,2-dimethylpropanoyl)-furo[2,3-b]pyridin-3-yl]-3-methylimidazolidin-2-one

To a solution of 55 mg (0.1 mmol) of the product from Step A dissolvedin 1.0 mL of THF was added 39.3 mg (0.15 mol) of triphenylphosphinefollowed by 25 mL (0.15 mmol) of diethylazodicarboxylate. The reactionmixture was stirred at room temperature overnight then evaporated invacuo. The residue was then purified on a silica gel flashchromatography column eluted with 0-40% EtOAc-hexane. Evaporation of thepurified fractions and drying in vacuo afforded the title compound.HPLC-MS: 522.0 (M+1), 523.9 (M+3); R_(t)=4.32 min.

EXAMPLE 85

1-[6-(2-Chlorophenyl)-5-(4-chlorophenyl)-2-(2-hydroxy-2-methylpropanoyl)furo[2,3-b]pyridin-3-yl-3-methylimidazolidine-2,4-dioneStep A: 2-Chloro-N-({[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2,2-5dimethylpropanoyl)furo[2,3-b]pyridin-3-yl]amino]carbonyl acetamide

To the product of Step B in Example 51 (0.250 g, 0.57 mmol) in 4 mL THFwas added 0.051 mL of chloroacetyl isocyanate. After 2.5 hours thereaction was concentrated and the residue purified via silica gel flashchromatography eluting with 0-25% ethyl acetate-hexane to afford thetitle compound. HPLC-MS: 557.9 (M+1), 559.9 (M+3); R_(t)=4.45 min.

Step B:1-[6-(2-Chlorophenyl)-5-(4-chlorophenyl)-2-(2-hydroxy-2-methyl-propanoyl)furo[2,3-b]pyridin-3-yl]-3-methylimidazolidine-2,4-dione

To the product of the Step A (0.260 g, 0.465 mmol) in 4 mL DMSO wasadded 42 mg of NaH (60% dispersion in mineral oil). After 1 h thereaction was diluted with ethyl acetate and washed with 10% aqueousNaHSO₄ solution and then saturated aqueous NaCl. The solution wasconcentrated affording the intermediate hydantoin which was thenmethylated by treating it with 460 mg Cs₂CO₃ in DMF (4 mL) and MeI(0.296 mL). After about 30 min the reaction mixture was diluted withethyl acetate and washed with saturated aqueous NaHCO₃ solution and thensaturated aqueous NaCl. The residue from the concentrated solution waspurified via silica gel flash chromatography eluting with a 0-25% ethylacetate-hexane to afford the product. HPLC-MS: 536.0 (M+1), 538.0 (M+3);R_(t)=4.26 min.

EXAMPLE 86

1-[6-(2-Chlorophenyl)-5-(4-chlorophenyl)-2-(2,2-dimethylpropanoyl)furo[2,3-b]pyridin-3-yl]-4-methylpiperazine-2,3-dioneStep A:N′-[6-(2-Chlorophenyl)-5-(4-chlorophenyl)-2-(2,2-dimethylpropanoyl)-furo[2,3-b]pyridin-3-yl]-N-(2-hydroxyethyl)-N-methylethanediamide

A 10 mL round bottom flask was charged with a solution of 0.136 g (0.31mmol) of the product of Step B in Example 51 dissolved in 2 mL CH₂Cl₂and 34 μL (0.39 mmol) of oxalyl chloride was added via syringe. Afterstirring 20 min at room temperature, approximately 70 mg (three-foldexcess) of 2-(methylamino)ethanol was added via syringe and the reactionmixture was stirred an additional 1.5 h. At this point the solvent wasevaporated and the residue was partitioned between EtOAc and 0.5 N HCl.The organic layer was separated, washed sequentially with 0.5 N HCl,water and brine, then dried (MgSO₄), filtered and evaporated. Theresidue was purified on a silica gel flash chromatography column elutedwith 0-50% EtOAc-hexane. Evaporation of the purified fractions anddrying in vacuo afforded the title compound. HPLC/MS: 568.0 (M+1), 569.9(M+3); R_(t)=4.28 min.

Step B:1-[6-(2-Chlorophenyl)-5-(4-chlorophenyl)-2-(2,2-dimethylpropanoyl)-furo[2,3-b]pyridin-3-yl]-4-methylpiperazine-2,3-dione

A 10 mL rb flask was charged with a solution of 0.075 g (0.13 mmol) ofthe product of Step A and 0.052 g (0.2 mmol) triphenylphosphine in 2 mLTHF. The reaction mixture was stirred at 0° C. and 39 μL ofdiisopropylazodicarboxylate was added dropwise. The reaction mixture wasstirred an additional 1 h at room temperature, then evaporated todryness. The residue was purified on a silica gel flash chromatographiccolumn eluted with 0-75% EtOAc-hexane. Evaporation of the purifiedfractions and drying in vacuo afforded the title compound. HPLC/MS:550.0 (M+1), 551.9 (M+3); R_(t)=3.95 min.

EXAMPLE 87

1-[6-(2-Chlorophenyl)-5-(4-chlorophenyl)-2-(2,2-dimethylpropanoyl)furo[2,3-b]pyridin-3-yl]-4-methylpiperazine-2,5-dioneStep A:N²-(Chloroacetyl)-N¹-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2,2-dimethylpropanoyl)furo[2,3-b]pyridin-3-yl]-N²-methylglycinamide

A solution of 0.127 g (0.25 mmol) of the product from Example 76 inCH₂Cl₂ (2 mL) at room temperature was treated with chloroacetyl chloride(29 μL; 0.375 mmol). After 15 minutes an additional aliquot ofchloroacetyl chloride (29 μL; 0.375 mmol) was added, and after 30 mintriethylamine (10 μL; 0.0718 mmol) was added. After stirring for 35minutes the reaction was quenched with saturated NaHCO₃ solution. Thereaction mixture was partitioned between methylene chloride andsaturated NaHCO₃ solution. The organic layer was concentrated in vacuoand purified by MPLC (silica gel; 0% to 70% ethyl acetate:hexanegradient) to afford the title compound. HPLC/MS: 586.0 (M+1), 588.0(M+3); R_(t)=4.35 min.

Step B:1-[6-(2-Chlorophenyl)-5-(4-chlorophenyl)-2-(2,2-dimethylpropanoyl)-furo[2,3-b]pyridin-3-yl]-4-methylpiperazine-2,5-dione

The product obtained from step A (0.140 g, 0.24 mmol) was dissolved inDMSO (4 mL) and 12 mg (0.28 mmol) of a 60% oil dispersion of sodiumhydride was added and the reaction mixture stirred for 2 h. The reactionwas quenched with saturated 10% NaHSO₄, partitioned with ethyl acetate,and washed with brine. The organic layer was separated, concentrated invacuo and purified by MPLC (silica gel; 0% to 100% ethyl acetate-hexanegradient) to afford the title compound. HPLC/MS: 550.2 (M+1), 552.2(M+3); R_(t)=3.93 min.

EXAMPLE 88

1-[6-(2-Chlorophenyl)-5-(4-chlorophenyl)-3-hydroxyfuro[2,3-b]pyridin-2-yl]-2,2-dimethylpropan-1-oneStep A:6-(2-Chlorophenyl)-5-(4-chlorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylicacid

A 500 mL rb flask was charged with 10.08 g (29.0 mmol) of the product ofStep B in Example 51 and 100 mL of 50% aqueous H₂SO₄ was added. Thesuspension was magnetically stirred in an oil bath and heated at 140° C.for 16 h. The reaction mixture was then cooled to room temperature,diluted with 300 mL of water and filtered. The filtered solids werewashed with water and dried in vacuo to afford the title compound whichwas used in the next step without further purification.

Step B: Methyl6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylate

A 250 mL rb flask equipped with a magnetic stir bar was charged with6.68 g (19.0 mmol) of the product of Step A, 100 mL methanol, 3 mL ofconcentrated sulfuric acid and the suspension was refluxed overnight.The resulting clear solution was then cooled to room temperature andevaporated. The residue was partitioned between EtOAc and 5% aqueousNa₂CO₃ and separated. The organic layer was washed with water, brine,dried (MgSO₄), filtered and evaporated to afford the title compound.

Step C: Methyl6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(3,3-dimethyl-2-oxobutoxy)nicotinate

A 25 mL rb flask was charged with 1.111 g (2.97 mmol) of the product ofStep B, 1.451 g (4.45 mmol) Cs₂CO₃, 10 mL DMF and finally 0.5 mL (3.71mmol) of bromopinacolone. The reaction mixture was stirred at roomtemperature 1 h then partitioned between EtOAc and water. The organiclayer was washed with water, brine, then dried (MgSO₄), filtered andevaporated. The residue was purified on a silica gel flashchromatography column eluted with 0-20% EtOAc-hexane. Evaporation of thepurified fractions and drying in vacuo afforded the title compound.

Step D:1-[6-(2-Chlorophenyl)-5-(4-chlorophenyl)-3-hydroxyfuro[2,3-b]pyridin-2-yl]:2,2-dimethylpropan-1-one

To an oven-dried 25 mL rb flask charged with a solution of 1.249 g (2.31mmol) of the product of Step C in 10 ml TBF was slowly added 2.64 mL ofa 1.0 N solution of lithium bis(trimethylsilylamide) in THF at 0° C. Thereaction mixture was stirred 1 h at 0° C. then quenched with excess 10%aq. NaHSO₄. The reaction mixture was extracted into EtOAc and separated.The organic layer was the washed with water, brine, dried (MgSO₄),filtered and evaporated to afford the title compound. HPLC/MS: 440.0(M+1), 442.0 (M+3); R_(t)=4.80 min.

EXAMPLE 89

1-[6-(2-Chlorophenyl)-5-(4-chlorophenyl)-3-methylfuro[2,3-b]pyridin-2-yl]-2,2-dimethylpropan-1-oneStep A: 3-Acetyl-6-(2-chlorophenyl)-5-(4-chlorophenyl)pyridin-2 (1H)-one

An oven-dried 500 mL rb flask was charged with a suspension of 15.02 g(44.0 mmol) of the product of Step B in Example 51 in 100 mL THF. Themixture was stirred under a nitrogen atmosphere and 70 mL of a 1.4 Msolution of methylmagnesium bromide in toluene/THF was slowly added over30 min via syringe. The reaction mixture warmed, becoming homogenousyellow-orange, and the addition was maintained at a rate to keep thetemperature below the boiling point of THF. After the addition wascomplete, the reaction stirred an additional 1 h at room temperature.The reaction mixture was then quenched with 1.0 N HCl and the organiclayer was separated and evaporated. The residue was redissolved in hotEtOAc and then washed with water, brine, dried (MgSO₄), filtered andevaporated in vacuo to afford the title compound which was used in thenext step without further purification.

Step B:1-{[3-Acetyl-6-(2-chlorophenyl)-5-(4-chlorophenyl)pyridin-2-yl]oxy}-3,3-dimethylbutan-2-one

To a 25 mL rb flask equipped with a magnetic stir bar was added 0.309g(0.86 mmol) of the product of Step A, 0.422 g (1.29 mmol) of cesiumcarbonate, 3 mL DMF and finally 145 μL of 1-bromopinacolone was added.The reaction mixture was stirred at room temperature for 1.5 h thenpartitioned between EtOAc and water. The organic layer was separated,washed with 10% aq. NaHSO₄, water, brine, dried (MgSO₄), filtered andevaporated. The residue was purified on s silica gel flashchromatography column eluted with 0-10% EtOAc-hexane. Evaporation of thepurified fractions and drying in vacuo afforded the title compound.

Step C:1-[6-(2-Chlorophenyl)-5-(4-chlorophenyl)-3-methylfuro[2,3-b]pyridin-2-yl]-2,2-dimethylpropan-1-one

A mixture of 0.432 g (0.95 mmol) of the product of Step B, 250 A (1.67mmol) of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in 2 mL DNF was placedin a 10 mL reaction tube of a CEM Corporation Discover 300 Wattmicrowave reactor. The reaction vessel was sealed, placed in themicrowave reactor and heated at 150° C. for 10 min. After the reactionmixture had cooled to room temperature, it was partitioned between EtOAcand 10% aq. NaHSO₄ and extracted. The organic layer was washed with 10%aq. NaHSO₄, water, brine, dried (MgSO₄), filtered and evaporated. Theresidue was purified on a silica gel flash chromatography column elutedwith 0-10% EtOAc-hexane. Evaporation of the purified fractions anddrying in vacuo afforded the title compound. HPLC/MS: 438.1 (M+1), 440.1(M+3); R_(t)=4.72 min.

EXAMPLE 90

6-(2-Chlorophenyl)-5-(4-chlorophenyl)-2-(2,2-dimethylpropanoyl)furo[2,3-b]pyridine-3-carbaldehyde

A 10 mL rb flask equipped with a magnetic stir bar was charged with0.227 g (0.52 mmol) of the product of Example 89, 0.101 g (0.57 mmol) ofN-bromosuccinimide, 3 mL CCl₄ and ca. 5 mg of2,2′-azobisisobutyronitrile (AIBN). The reaction mixture was heated toreflux under a nitrogen atmosphere for 2 h then cooled to roomtemperature and filtered. The filtrate was evaporated in vacuo, and theresidue was then redissolved in 2 mL of DMSO. The solution containingthe crude bromination product was transferred to a 10 mL reaction tubeof a CEM Corporation Discover 300 Watt microwave reactor and 73 mg (0.62mmol) of N-methylmorpholine-N-oxide was added. The reaction vessel wassealed, placed in the microwave reactor and heated at 150° C. for 2-3min. After the reaction mixture had cooled to room temperature, it waspartitioned between EtOAc and 10% aq. NaHSO₄ and extracted. The organiclayer was washed with 10% aq. NaHSO₄, water, brine, dried (MgSO₄),filtered and evaporated. The residue was purified on a silica gel flashchromatography column eluted with 0-10% EtOAc-hexane. Evaporation of thepurified fractions and drying in vacuo afforded the title compound.HPLC/MS: 452.1 (M+1), 454.0 (M+3); R_(t)=4.63 min.

EXAMPLE 91

Methyl6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2,2-dimethylpropanoyl)furo[2,3-b]pyridine-3-carboxylate

A 10 mL rb flask equipped with a magnetic stir bar and a septum wascharged with a solution of 50 mg (0.11 mmol) of the product of Example90, in 2 mL MeOH, 24 mg (0.27 mmol) of manganese dioxide and ca. 5 mg ofsodium cyanide was added. The reaction mixture was stirred at roomtemperature for 4 h, then filtered and evaporated in vacuo. The residuewas purified on a silica gel flash chromatography column eluted with0-10% EtOAc-hexane. Evaporation of the purified fractions and drying invacuo afforded the title compound. HPLC/MS: 482.2 (M+1), 484.0 (M+3);R_(t)=4.57 min.

EXAMPLE 92

6-(2-Chlorophenyl)-5-(4-chlorophenyl)-2-(2,2-dimethylpropanoyl)-N,N-diethylfuro-[2,3-b]pyridine-3-carboxamide

Reaction of trimethylaluminum with diethylamine according to Weinreb'sprocedure (Basha, A.; Lipton, M.; Weinreb, S. M. Tetrahedron Lett, 1977,48, 4171-4174) affords N,N-diethyl-aluminum which in turn may be reactedwith the product of Example 91 to afford the title compound.

EXAMPLE 93

1-[6-(2-Chlorophenyl)-5-(4-chlorophenyl)-3-(4H-1,2,4-triazol-4-yl)furo[2,3-b]-pyridin-2-yl}-2,2-dimethylpropan-1-one

To a solution of 110 mg (0.25 mmol) of the product of Step B in Example51 dissolved in 1 mL of toluene, 80 mg (0.56 mmol) ofN-(dimethylamino)methylene-N,N-dimethylhydrazonoformamide and 5 mg(0.026 mmol)of p-toluenesulfonic acid were added. The vial was tightlycapped and heated in a 105° C. oil bath for 4 days. The reaction wascooled, diluted with EtOAc, washed with water and brine. The organiclayer was dried and concentrated. The residue was purified by prep TLCusing 50% EtOAc/hexane to isolate the title compound. HPLC/MS: 491(M+1), 493 (M+3); R_(t)=3.94 min.

EXAMPLE 94

1-[6-(2-Chlorophenyl)-5-(4-chlorophenyl)furo[2,3-b]pyridin-2-yl]-2,2-dimethylpropan-1-oneStep A: 6-(2-Chlorophenyl)-5-(4-chlorophenyl)-3-formyl-2-pyridone

A solution of 0.34 g (1 mmol) of the product of Step B in Example 51dissolved in 4 mL of dry THF was cooled to −78° C. in a dry ice-acetonebath and 1.5 mL of 1.5 M diisobutylaluminum hydride (DIBAL) in toluenewas added. After 15 min the cold bath was removed and the mixture wasallowed to warm to room temperature, while all the solids dissolved.After 5 h, the reaction was quenched with 1.2 N HCl and extracted withEtOAc. The organic layer was washed with brine, dried and concentratedto afford 0.38 g of the title compound which was used in the next stepwithout further purification.

Step B:1-[6-(2-Chlorophenyl)-5-(4-chlorophenyl)furo[2,3-b]pyridin-2-yl]-2,2-dimethylpropan-1-one

To a solution of 0.38 g of the product of Step A dissolved in 3 mL ofDW, was added 0.14 mL (1.07 mmol) of 1-chloropinacolone and 0.65 g ofCs₂CO₃. After stirring for 2 h, another 0.05 mL (0.38 mmol) of1-chloropinacolone was added and the stirring was continued for another1 h. Additional 0.325 g (1 mmol) of Cs₂CO₃ was added and the solutionwas heated in a 60° C. bath for 3 h. The solution was cooled, dilutedwith Et₂O, washed with water, brine, dried and concentrated. The residuewas purified on a prep TLC plate using 20% EtOAc/hexane as eluant toafford the title compound. HPLC/MS: 424 (M+1), 426 (M+3); R_(t)=4.49min.

EXAMPLE 95

1-[6-(2-Chlorophenyl)-5-(4-chlorophenyl)-3-(pyridin-2-ylamino)furo[2,3-b]pyridin-2-yl]-2,2-dimethylpropan-1-one

A flask containing 80 mg (0.51 mmol) 2-bromopyridine, 2.3 mg (0.01 mmol)of Pd(OAc)₂, and 9.5 mg (0.015 mmol) of BINAP was flushed with N₂ and asolution of 267 mg (0.61 mmol) of the product of Step B in Example 51dissolved in 2 mL of toluene was added. After 5 min, 231 mg (0.71 mmol)of Cs₂CO₃ was added and the mixture was heated in a 105° C. bath for 3days. The reaction was cooled, diluted with EtOAc, and washed with waterand brine. The organic layer was dried, concentrated and the residue waspurified on a prep TLC plate using 10% EtOAc/hexane as eluant to afford235 mg of the title compound. BPLC/MS: 516 (M+1), 518 (M+3); R_(t)=4.67min.

EXAMPLES 96-99

Using procedure described in Example 95, the product of Example 51 wasreacted with the appropriate halo-substituted heterocyclic compound toafford the following compounds: HPLC/MS Example Name m/z; R_(t): 961-[6-(2-Chlorophenyl)-5-(4-chlorophenyl)-3-(pyrimidin-2- 517 (M + 1),ylamino)-furo[2,3-b]pyridin-2-yl]-2,2-dimethylpropan-1-one 519 (M + 3);4.80 min 97 1-[6-(2-Chlorophenyl)-5-(4-chlorophenyl)-3-(pyrimidin-5- 517(M + 1), ylamino)-furo[2,3-b]pyridin-2-yl]-2,2-dimethylpropan-1-one 519(M + 3); 4.29 min 981-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-3-(pyridin-3- 516 (M + 1),ylamino)-furo[2,3-b]pyridin-2-yl]-2,2-dimethylpropan-1-one 518 (M + 3);3.46 min 99 1-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-3-(pyridin-4- 516(M + 1), ylamino)-furo[2,3-b]pyridin-2-yl]-2,2-dimethylpropan-1-one 518(M + 3); 3.25 min

EXAMPLE 100

1-[3-Amino-6-(2-chlorophenyl)-5-(4-chlorophenyl)furo[2,3-b]pyridin-2-yl]-2-hydroxy-2-methylpropan-1-oneStep A: 1-Bromo-3-hydroxy-3-methylbutan-2-one

To a solution of 12.0 g of 3-hydroxy-3-methyl-2-butanone in 100 mLdiethylether was added 18.78 g of bromine at room temperature. After afew minutes a strong exothermic reaction began which necessitatedice/water cooling and the reaction color changed from dark red to lightorange. The reaction mixture was then concentrated and repeatedlydissolved in diethyl ether and reevaporated 4 times to afford the titlecompound which was used in the next step without further purification.

Step B:1-[3-Amino-6-(2-chlorophenyl)-5-(4-chlorophenyl)furo[2,3-b]pyridin-2-yl]-2-hydroxy-2-methylpropan-1-one

To a solution of 8.82 g of the product from Step B in Example 51 in 85mL DMF was added 14.0 g (3-eq.) of the product of Step A and 19.6 g ofpotassium carbonate. The reaction mixture was stirred at roomtemperature for 10 min then heated to 60° C. After 65 minutes at 60° C.the reaction mixture was allowed to cool to room temperature and stirredovernight. LC/MS showed incomplete cyclization so an additional 5.8 g ofpotassium carbonate were added and the mixture heated for 40 minutes at65° C. to complete the cyclization. The reaction mixture was dilutedwith ethyl acetate, filtered, and washed with brine. The washed solutionwas concentrated to between 100 and 150 mL then passed through 80 mL ofsilica on a fritted filter funnel, washing with ethyl acetate. Thematerial was purified on a silica gel flash chromatography column elutedwith 0-60% ethyl acetate in hexanes. Evaporation of the purifiedfractions afforded the title compound. HPLC/MS: 441.0 (M+1), 442.9(M+3); R_(t)=3.89 min.

EXAMPLE 101

N-[6-(2-Chlorophenyl)-5-(4-chlorophenyl)-2-(2-hydroxy-2-methylpropanoyl)furo[2,3-b]pyridin-3-yl]-2-hydroxyacetamideStep A:2-{[6-(2-Chlorophenyl)-5-(4-chlorophenyl)-2-(2-hydroxy-2-methylpropanoyl)furo[2,3-b]pyridin-3yl]amino}-2-oxoethylacetate

To a solution of 4.0 g of the product of Example 100 in 25 mL ofacetonitrile was added 7.5 mL acetoxy acetylchloride and the reactionmixture was stirred at room temperature. After 50 min the reactionmixture was diluted with CH₂Cl₂ and washed two times with aqueous sodiumbicarbonate. The organic layer was dried over sodium sulfate thenconcentrated. The residue was suspended in 150 mL of methanol at 60-65°C. After cooling to room temperature the methanol was decanted away andthe solid rinsed three times with fresh methanol. The solids were thendried in vacuo to afford the title compound. HPLC/MS: 540.9 (M+1), 542.8(M+3); R_(t)=4.07 min.

Step B:N-[6-(2-Chlorophenyl)-5-(4-chlorophenyl)-2-(2-hydroxy-2-methylpropanoyl)furo[2,3-b]pyridin-3-yl]-2-hydroxyacetamide

Lithium hydroxide-H₂O (0.293 g), the product of Step A (3.78 g), andmethanol (8.4 mL) were combined in 245 mL of TBF and stirred at roomtemperature. After 5 min 0.50 mL of acetic acid was added and thesolution concentrated. The residue was diluted with ethyl acetate andthis solution washed two times with aqueous sodium bicarbonate. Thesolution was concentrated and purified via flash chromatography onsilica gel with a gradient elution of 0 to 55% ethyl acetate inmethylene chloride. The product was then further purified byrecrystallization from ethanol to afford the title compound. HPLC/MS:499.0 (M+1), 500.8 (M+3); R_(t)=3.77 min.

EXAMPLE 102

N-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2-hydroxy-2-methylpropanoyl)furo[2,3-b]pyridin-3-yl]acetamide

The product of Example 100 (0.200 g), acetic anhydride (1.25 mL) andacetic acid (0.25 mL) were combined and then heated to 85° C. After 3 hthe reaction was concentrated and the residue was dissolved indichloromethane and washed twice with aqueous sodium bicarbonate. Thesolution was then concentrated and the residue was purified via flashchromatography on silica gel with gradient elution of 0-60% ethylacetate in hexanes affording the title compound. HPLC/MS: 483.0 (M+1),484.8 (M+3); R_(t)=3.95-min.

EXAMPLES 103-139

Starting with the product of Example 100 and using the proceduresdescribed in reaction Schemes 6-8 and in the preceding Examples, thefollowing additional compounds were prepared: HPLC/MS Example Name m/z;R_(t): 103 N-[6-(2-Chlorophenyl)-5-(4-chlorophenyl)-2-(2-hydroxy- 509.0(M + 1), 2-methylpropanoyl)furo[2,3-b]pyridin-3- 511.0 (M + 3);yl]cyclopropanecarboxamide 4.30 min 104N-[6-(2-Chlorophenyl)-5-(4-chlorophenyl)-2-(2-hydroxy- 510.9 (M + 1),2-methylpropanoyl)furo[2,3-b]pyridin-3-yl]-2- 512.9 (M + 3);methylpropanamide 4.40 min 105N-[6-(2-Chlorophenyl)-5-(4-chlorophenyl)-2-(2-hydroxy- 525.0 (M + 1),2-methylpropanoyl)furo[2,3-b]pyridin-3-yl]-3- 527.0 (M + 3);methylbutanamide 4.55 min 106N-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2-hydroxy- 510.9 (M + 1),2-methylpropanoyl)furo[2,3-b]pyridin-3-yl]butanamide 512.8 (M + 3); 4.40min 107 N-[6-(2-Chlorophenyl)-5-(4-chlorophenyl)-2-(2-hydroxy- 496.9(M + 1), 2-methylpropanoyl)furo[2,3-b]pyridin-3-yl]propanamide 498.9(M + 3); 4.22 min 108N-[6-(2-Chlorophenyl)-5-(4-chlorophenyl)-2-(2-hydroxy- 512.9 (M + 1),2-methylpropanoyl)furo[2,3-b]pyridin-3-yl]-2- 514.8 (M + 3);methoxyacetamide 4.13 min 109N-[6-(2-Chlorophenyl)-5-(4-chlorophenyl)-2-(2-hydroxy- 527.0 (M + 1),2-methylpropanoyl)furo[2,3-b]pyridin-3-yl]-2-hydroxy-2- 529.0 (M + 3);methylpropanamide 4.05 min 1104-Chloro-N-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2- 544.8 (M + 1),hydroxy-2-methylpropanoyl)furo[2,3-b]pyridin-3- 546.8 (M + 3);yl]butanamide 4.29 min 1111-[6-(2-Chlorophenyl)-5-(4-chlorophenyl)-2-(2-hydroxy- 508.9 (M + 1),2-methylpropanoyl)furo[2,3-b]pyridin-3-yl]pyrrolidin-2- 510.9 (M + 3);one 3.79 min 112 N-[6-(2-Chlorophenyl)-5-(4-chlorophenyl)-2-(2-hydroxy-519.8 (M + 1), 2-methylpropanoyl)furo[2,3-b]pyridin-3-yl]sulfamide 521.8(M + 3); 3.75 min 1132-Chloro-N-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2- 516.9 (M + 1),hydroxy-2-methylpropanoyl)furo[2,3-b]pyridin-3- 518.8 (M + 3);yl]acetamide 4.19 min 114N¹-[6-(2-Chlorophenyl)-5-(4-chlorophenyl)-2-(2- 512.0 (M + 1),hydroxy-2-methylpropanoyl)furo[2,3-b]pyridin-3-yl]-N²- 514.0 (M + 3);methylglycinamide 2.98 min 115N²-Acetyl-N¹-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2- 554.0 (M + 1),(2-hydroxy-2-methylpropanoyl)furo[2,3-b]pyridin-3-yl]- 556.0 (M + 3);N²-methylglycinamide 3.67 min 1162-Azetidin-1-yl-N-[6-(2-chlorophenyl)-5-(4- 538.0 (M + 1),chlorophenyl)-2-(2-hydroxy-2-methylpropanoyl)furo[2,3- 540.0 (M + 3);b]pyridin-3-yl]acetamide 3.02 min 117N-[6-(2-Chlorophenyl)-5-(4-chlorophenyl)-2-(2-hydroxy- 548.9 (M + 1),2-methylpropanoyl)furo[2,3-b]pyridin-3-yl]-2-(1H- 550.9 (M + 3);imidazol-1-yl)acetamide 3.06 min 1181-[6-(2-Chlorophenyl)-5-(4-chlorophenyl)-2-(2-hydroxy- 523.1 (M + 1),2-methylpropanoyl)furo[2,3-b]pyridin-3-yl]pyrrolidine- 525.0 (M + 3);2,5-dione 3.75 min 119 Methyl3-{[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2- 541.0 (M + 1),hydroxy-2-methylpropanoyl)furo[2,3-b]pyridin-3- 542.9 (M + 3);yl]amino}-3-oxopropanoate 4.00 min 120N²-[6-(2-Chlorophenyl)-5-(4-chlorophenyl)-2-(2- 526.0 (M + 1),hydroxy-2-methylpropanoyl)furo[2,3-b]pyridin-3-yl]- 527.9 (M + 3);N¹,N¹-dimethylglycinamide 3.84 min 121 Ethyl[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2- 513.0 (M + 1),hydroxy-2-methylpropanoyl)furo[2,3-b]pyridin-3- 514.8 (M + 3);yl]carbamate 4.43 min 122N′-[6-(2-Chlorophenyl)-5-(4-chlorophenyl)-2-(2-hydroxy- 540.8 (M + 1),2-methylpropanoyl)furo[2,3-b]pyridin-3-yl]-N,N- 541.9 (M + 3);dimethylethanediamide 4.09 min 123N-[6-(2-Chlorophenyl)-5-(4-chlorophenyl)-2-(2-hydroxy- 526.0 (M + 1),2-methylpropanoyl)furo[2,3-b]pyridin-3-yl]-N′- 528.0 (M + 3);methylethanediamide 3.93 min 124N-[6-(2-Chlorophenyl)-5-(4-chlorophenyl)-2-(2-hydroxy- 556.0 (M + 1),2-methylpropanoyl)furo[2,3-b]pyridin-3-yl]-N′-(2- 558.0 (M + 3);hydroxyethyl)ethanediamide 3.65 min 125N-[6-(2-Chlorophenyl)-5-(4-chlorophenyl)-2-(2-hydroxy- 540.0 (M + 1),2-methylpropanoyl)furo[2,3-b]pyridin-3-yl]-N′- 541.9 (M + 3);ethylethanediamide 4.11 min 126N-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2-hydroxy- 566.0 (M + 1),2-methylpropanoyl)furo[2,3-b]pyridin-3-yl]-2-oxo-2- 568.0 (M + 3);pyrrolidin-1-ylacetamide 4.32 min 127N-[6-(2-Chlorophenyl)-5-(4-chlorophenyl)-2-(2-hydroxy- 512.0 (M + 1),2-methylpropanoyl)furo[2,3-b]pyridin-3-yl]-N′-ethylurea 514.0 (M + 3);4.05 min 128 N-[6-(2-Chlorophenyl)-5-(4-chlorophenyl)-2-(2-hydroxy-554.0 (M + 1), 2-methylpropanoyl)furo[2,3-b]pyridin-3-yl]morpholine-4-556.0 (M + 3); carboxamide 4.01 min 129N-[6-(2-Chlorophenyl)-5-(4-chlorophenyl)-2-(2-hydroxy- 538.1 (M + 1),2-methylpropanoyl)furo[2,3-b]pyridin-3-yl]pyrrolidine-1- 540.1 (M + 3);carboxamide 4.29 min 130 1-[6-(2-Chlorophenyl)-5-(4-chlorophenyl)-3-455.0 (M + 1), (methylamino)furo[2,3-b]pyridin-2-yl]-2-hydroxy-2- 457.0(M + 3); methylpropan-1-one 4.10 min 1311-[6-(2-Chlorophenyl)-5-(4-chlorophenyl)-2-(2-hydroxy- 524.0 (M + 1),2-methylpropanoyl)furo[2,3-b]pyridin-3-yl]imidazolidine- 525.9 (M + 3);2,4-dione 3.54 min 1321-[6-(2-Chlorophenyl)-5-(4-chlorophenyl)-2-(2-hydroxy- 524.0 (M + 1),2-methylpropanoyl)furo[2,3-b]pyridin-3-yl]-3- 525.9 (M + 3);methylimidazolidin-2-one 3.78 min 1331-[6-(2-Chlorophenyl)-5-(4-chlorophenyl)-2-(2-hydroxy- 538.0 (M + 1),2-methylpropanoyl)furo[2,3-b]pyridin-3-yl]-3- 539.9 (M + 3);methylimidazolidine-2,4-dione 3.75 min 1343-[6-(2-Chlorophenyl)-5-(4-chlorophenyl)-2-(2-hydroxy- 511.0 (M + 1),2-methylpropanoyl)furo[2,3-b]pyridin-3-yl]-1,3- 512.9 (M + 3);oxazolidin-2-one 3.70 min 135N-[6-(2-Chlorophenyl)-5-(4-chlorophenyl)-2-(2-hydroxy- 568.2 (M + 1),2-methylpropanoyl)furo[2,3-b]pyridin-3-yl]-N′,2,2- 570.1 (M + 3);trimethylmalonamide 3.91 min 136N-[6-(2-Chlorophenyl)-5-(4-chlorophenyl)-2-(2-hydroxy- 538.1 (M + 1),2-methylpropanoyl)furo[2,3-b]pyridin-3-yl]-(S)- 540.1 (M + 3);prolinamide 3.07 min 1371-[6-(2-Chlorophenyl)-5-(4-chlorophenyl)-3-(1,1- 545.1 (M + 1),dioxidoisothiazolidin-2-yl)furo[2,3-b]pyridin-2-yl]-2- 547.0 (M + 3);hydroxy-2-methylpropan-1-one 3.83 min 138N-[6-(2-Chlorophenyl)-5-(4-chlorophenyl)-2-(2-hydroxy- 554.2 (M + 1),2-methylpropanoyl)furo[2,3-b]pyridin-3-yl]-2,2- 556.2 (M + 3);dimethylmalonamide 3.78 min 1391-[6-(2-Chlorophenyl)-5-(4-chlorophenyl)-3- 440.1 (M + 1),methylfuro[2,3-b]pyridin-2-yl]-2-hydroxy-2- 442.1 (M + 3);methylpropan-1-one 4.14 min

EXAMPLE 140

1-[3-Amino-6-(2-chlorophenyl)-5-(4-chlorophenyl)furo[2,3-b]pyridin-2-yl]-2-methylpropan-1-one

To a solution of 2.39 g (7.0 mmol) of the product of Step A in Example51 in 25 mL DMF was added 7 g (21.5 mmol) Cs₂CO₃ and 1.2 g (7.3 mmol) of1-bromo-3-methylbutan-2-one. The reaction was stirred 1.5 h at roomtemperature and then 1 h at 60° C. The reaction mixture was concentratedand then diluted with ethyl acetate and washed with saturated NaClsolution. The residue from the concentrated solution was purified viasilica gel flash chromatography eluting with a gradient of 043% ethylacetate/hexane to afford the title compound. HPLC/MS: 425.1 (M+1), 427.2(M+3); R_(t)=4.30 min.

EXAMPLES 141-156

Starting with the product of Example 140 and using the proceduresdescribed in reaction Schemes 6-8 and in the preceding Examples, thefollowing additional compounds were prepared: HPLC/MS Example Name m/z;R_(t): 141 2-{[6-(2-Chlorophenyl)-5-(4-chlorophenyl)-2- 525.0 (M + 1),isobutyrylfuro[2,3-b]pyridin-3-yl]amino}-2-oxoethyl acetate 526.8 (M +3); 4.53 min 142 N-[6-(2-Chlorophenyl)-5-(4-chlorophenyl)-2- 483.2 (M +1), isobutyrylfuro[2,3-b]pyridin-3-yl]-2-hydroxyacetamide 485.2 (M + 3);4.24 min 143 N-[6-(2-Chlorophenyl)-5-(4-chlorophenyl)-2- 497.0 (M + 1),isobutyrylfuro[2,3-b]pyridin-3-yl]-2-hydroxy-N- 498.9 (M + 3);methylacetamide 3.94 min 144 N-[6-(2-Chlorophenyl)-5-(4-chlorophenyl)-2-467.0 (M + 1), isobutyrylfuro[2,3-b]pyridin-3-yl]acetamide 468.9 (M +3); 4.47 min 145 4-Chloro-N-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-528.9 (M + 1), isobutyrylfuro[2,3-b]pyridin-3-yl]butanamide 530.9 (M +3); 4.73 min 146 1-[6-(2-Chlorophenyl)-5-(4-chlorophenyl)-2- 493.1 (M +1), isobutyrylfuro[2,3-b]pyridin-3-yl]pyrrolidin-2-one 495.1 (M + 3);4.11 min 147 N-[6-(2-Chlorophenyl)-5-(4-chlorophenyl)-2- 481.0 (M + 1),isobutyrylfuro[2,3-b]pyridin-3-yl]-N-methylacetamide 482.9 (M + 3); 4.14min 148 1-[6-(2-Chlorophenyl)-5-(4-chlorophenyl)-2- 507.2 (M + 1),isobutyrylfuro[2,3-b]pyridin-3-yl]pyrrolidine-2,5-dione 509.2 (M + 3);4.07 min 149 4-[6-(2-Chlorophenyl)-5-(4-chlorophenyl)-2- 523.1 (M + 1),isobutyrylfuro[2,3-b]pyridin-3-yl]morpholine-3,5-dione 525.1 (M + 3);4.17 min 150 N-[6-(2-Chlorophenyl)-5-(4-chlorophenyl)-2- 503.0 (M + 1),isobutyrylfuro[2,3-b]pyridin-3-yl]methanesulfonamide 505.0 (M + 3); 4.28min 151 1-[6-(2-Chlorophenyl)-5-(4-chlorophenyl)-2- 508.0 (M + 1),isobutyrylfuro[2,3-b]pyridin-3-yl]imidazolidine-2,4-dione 509.9 (M + 3);3.93 min 152 N-[6-(2-Chlorophenyl)-5-(4-chlorophenyl)-2- 468.1 (M + 1),isobutyrylfuro[2,3-b]pyridin-3-yl]urea 470.1 (M + 3); 4.06 min 1531-[6-(2-Chlorophenyl)-5-(4-chlorophenyl)-2- 521.1 (M + 1),isobutyrylfuro[2,3-b]pyridin-3-yl]piperidine-2,6-dione 523.1 (M + 3);4.12 min 154 3-[6-(2-Chlorophenyl)-5-(4-chlorophenyl)-2- 519.1 (M + 1),isobutyrylfuro[2,3-b]pyridin-3-yl]-3- 521.0 (M + 3);azabicyclo[3.1.0]hexane-2,4-dione 4.19 min 1551-[6-(2-Chlorophenyl)-5-(4-chlorophenyl)-3-(1,1- 529.2 (M + 1),dioxidoisothiazolidin-2-yl)furo[2,3-b]pyridin-2-yl]-2- 531.1 (M + 3);methylpropan-1-one 4.18 min 156N-[6-(2-Chlorophenyl)-5-(4-chlorophenyl)-2- 517.1 (M + 1),isobutyrylfuro[2,3-b]pyridin-3-yl]-N- 519.0 (M + 3);methylmethanesulfonamide 4.28 min

EXAMPLE 157

[3-Amino-6-(2-chlorophenyl)-5-(4-chlorophenyl)furo[2,3-b]pyridin-2-yl](pyridin-3-yl)methanone

Using the procedure described in Example 26, the product of Step B inExample 51 was reacted with 3-(bromoacetyl)pyridine hydrobromide toafford the title compound. HPLC/MS: 460.0 (M+1), 462.0 M+3); R_(t) 3.28min.

EXAMPLE 158

N-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(pyridin-3-ylcarbonyl)furo[2,3-b]pyridin-3-yl]-2-hydroxyacetamide

Using the general acylating procedure described in Example 18, theproduct of Example 157 was reacted with acetoxyacetyl chloride and thensubjected to the general ester hydrolysis procedure described in Example25 to afford the title compound. HPLC/MS: 518.0 (M+1), 520.0 (M+3);R_(t)=3.52 min.

EXAMPLE 159

[3-amino-6-(2-chlorophenyl)-5-(4-chlorophenyl)furo[2,3-b]pyridin-2-yl](2-furyl)-methanone

Using the procedure described in Example 26, the product of Step B inExample 51 was reacted with 2-bromo-1-(2-furyl)ethanone to afford thetitle compound. BPLC/MS: 448.9 (M+1), 450.7 (M+3); R_(t)=4.03 min.

EXAMPLES 160 & 161

Using the procedure described in Example 2, the product of Example 159was reacted with acetyl chloride to afford Example 160. Alkalinehydrolysis of the product of Example 160 then afforded the titlecompound in Example 161: HPLC/MS Example Name m/z; R_(t): 160N-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2- 490.8 (M + 1),(2-furoyl)furo[2,3-b]pyridin-3-yl]acetamide 492.8 (M + 3); (R⁵, R⁶ =acetyl) 4.26 min 161 N-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2- 532.9(M + 1), (2-furoyl)furo[2,3-b]pyridin-3-yl]acetamide 534.9 (M + 3); (R⁵= acetyl, R⁶ = H) 4.07 min

EXAMPLE 162

2-(Tert-butylsulfonyl)-6-(2-chlorophenyl)-5-(4-chlorophenyl)furo[2,3-b]pyridin-3-amineStep A:2-[(Tert-butylthio)methoxy]-6-(2-chlorophenyl)-5-(4-chlorophenyl)-nicotinonitrile

To a solution of 3.0 g (8.80 mmol) of the product of Step B in Example51 in 15 mL DMF was added 3.44 g (10.6 mmol) of Cs₂CO₃ and a solutioncontaining approximately 1.34 g (9.7 mmol) oftert-butyl(chloromethyl)sulfide in 4.3 g of toluene. The reaction wasstirred 17 h at room temperature, then concentrated in vacuo. Theresidue was diluted with ethyl acetate and washed with saturated NaClsolution. The organic layer was evaporated again and then purified on asilica gel flash chromatography column eluting with a gradient of0.0-30% ethyl acetate/hexane to afford the title compound.

Step B:2-[(Tert-butylsulfonyl)methoxy]-6-(2-chlorophenyl)-5-(4-chlorophenyl)-nicotinonitrile

To a solution of product from Step A in 10 mL CH₂Cl₂ was added asolution of 2.6 g of (85 weight %) 3-chloroperoxybenzoic acid in 20 mLof acetonitrile. The reaction mixture was stirred for 25 min then it wasdiluted with ethyl acetate and washed with saturated NaHCO₃ solution.The residue from the concentrated solution was purified via silica gelflash chromatography eluting with a gradient of 0 to 40% ethylacetate/hexane to afford the title compound.

Step C:2-(Tert-butylsulfonyl)-6-(2-chlorophenyl)-5-(4-chlorophenyl)furo[2,3-b]pyridin-3-amine

To a stirred solution of 1.87 g (3.9 mmol) of the product of Step B in24 mL of DMF at 0° C. was added 7.9 mL of a 1.0 M solution of lithiumbis(trimethylsilyl) amide in THF. The reaction mixture was stirred anaddition 5 min then it was quenched with 0.45 mL of acetic acid and thenpartitioned between ethyl acetate and saturated NaCl solution. Theorganic layer was separated, dried (MgSO₄), filtered and evaporated. Theresidue was then purified via silica gel flash chromatography elutingwith a gradient of 0 to 40% ethyl acetate/hexane to afford the titlecompound. HPLC/MS: 475.1 (M+1), 477.0 (M+3); R_(t)=3.99 min.

EXAMPLES 163-171

Starting with the product of Example 162 and using the proceduresdescribed in reaction Schemes 6-8 and in the preceding Examples, thefollowing additional compounds were prepared: HPLC/MS Example Name m/z;R_(t): 163N-[2-(Tert-butylsulfonyl)-6-(2-chlorophenyl)-5-(4-chlorophenyl)- 553.1(M + 1), furo[2,3-b]pyridin-3-yl]methanesulfonamide 555.0 (M + 3); 4.06min 164 N-[2-(Tert-butylsulfonyl)-6-(2-chlorophenyl)-5-(4- 559.2 (M +1), chlorophenyl)-furo[2,3-b]pyridin-3-yl]acetimide 561.2 (M + 3); 4.10min 165 N-[2-(Tert-butylsulfonyl)-6-(2-chlorophenyl)-5-(4- 517.1 (M +1), chlorophenyl)-furo[2,3-b]pyridin-3-yl]acetamide 519.0 (M + 3); 4.05min 1662-{[2-(Tert-butylsulfonyl)-6-(2-chlorophenyl)-5-(4-chlorophenyl)- 575.2(M + 1), furo[2,3-b]pyridin-3-yl]amino}-2-oxoethyl acetate 577.1 (M +3); 4.15 min 167 N-[2-(Tert-butylsulfonyl)-6-(2-chlorophenyl)-5-(4-533.1 (M + 1), chlorophenyl)-furo[2,3-b]pyridin-3-yl]-2- 535.0 (M + 3);hydroxyacetamide 3.91 min 1681-[6-(2-Chlorophenyl)-5-(4-chlorophenyl)-2-(methylsulfonyl)- 515.1 (M +1), furo[2,3-b]pyridin-3-yl]pyrrolidine-2,5-dione 517.1 (M + 3); 3.74min 169 N-[2-(Tert-butylsulfonyl)-6-(2-chlorophenyl)-5-(4-chlorophenyl)-566.9 (M + 1), furo[2,3-b]pyridin-3-yl]-N- 568.9 (M + 3);methylmethanesulfonamide 4.08 min 170N-[2-(Tert-butylsulfonyl)-6-(2-chlorophenyl)-5-(4- 531.0 (M + 1),chlorophenyl)-furo[2,3-b]pyridin-3-yl]-N-methylacetamide 533.0 (M + 3);3.92 min 1711-[2-(Tert-butylsulfonyl)-6-(2-Chlorophenyl)-5-(4-chlorophenyl)- 558.2(M + 1), furo[2,3-b]pyridin-3-yl]imidazolidine-2,4-dione 560.1 (M + 3);3.77 min

EXAMPLES 172-176

Starting with the product of Step B in Example 51 andchloromethylphenylsulfide and using procedures described for thepreparation of the 2-tert-butylsulfonyl substituted furo[2,3-b]pyridinesof Examples 162-171, the following 2-phenylsulfonyl substitutedcompounds were prepared: HPLC/MS Example Name m/z; R_(t): 1726-(2-Chlorophenyl)-5-(4-chlorophenyl)-2- 495.0 (M + 1),(phenylsulfonyl)furo[2,3-b]pyridin-3-amine 497.0 (M + 3); 4.11 min 1732-{[6-(2-Chlorophenyl)-5-(4-chlorophenyl)- 595.1 (M + 1),2-(phenylsulfonyl)furo[2,3-b]pyridin-3-yl] 597.0 (M + 3);amino}-2-oxoethyl acetate 4.23 min 174 N-[6-(2-Chlorophenyl)-5- 553.0(M + 1), (4-chlorophenyl)-2-(phenylsulfonyl)furo 555.0 (M + 3);[2,3-b]pyridin-3-yl]-2-hydroxyacetamide 4.02 min 1752-Chloro-N-({[6-(2-chlorophenyl)-5- 614.0 (M + 1),(4-chlorophenyl)-2-(phenylsulfonyl)furo 616.0 (M + 3);[2,3-b]pyridin-3-yl]amino}carbonyl) 4.16 min 1761-[6-(2-Chlorophenyl)-5-(4-chlorophenyl)-2- 578.1 (M + 1),acetamide(phenylsulfonyl)furo[2,3-b] 580.1 (M + 3);pyridin-3-yl]imidazolidine-2,4-dione 3.87 min

EXAMPLES 177-179

Starting with the product of Step B in Example 51 andchloromethylphenylsulfide and using procedures described for thepreparation of the 2-tert-butylsulfonyl substituted furo[2,3-b]pyridinesof Examples 162-171, the following 2-methylsulfonyl substitutedcompounds were prepared: HPLC/MS Example Name m/z; R_(t): 1776-(2-Chlorophenyl)-5-(4-chlorophenyl)-2- 433.0 (M + 1),(methylsulfonyl)furo[2,3-b]pyridin-3-amine 435.0 (M + 3); 3.74 min 178N-[6-(2-Chlorophenyl)-5-(4-chlorophenyl)-2- 475.0 (M + 1),(methylsulfonyl)-furo[2,3-b] yridine-3-yl] 477.0 (M + 3); acetamide 3.72min 179 N-[6-(2-Chlorophenyl)-5-(4-chlorophenyl)-2- 503.1 (M + 1),(methylsulfonyl)-furo[2,3-b]pyridin-3-yl] 505.1 (M + 3); butanamide 4.05min

EXAMPLE 180

Ethyl3-amino-6-(2-chlorophenyl)-5-(4-chlorophenyl)furo[2,3-b]pyridine-2-carboxylateStep A:Ethyl{[6-(2-chlorophenyl)-5-(4-chlorophenyl)-3-cyanopyridin-2-yl]oxy}acetate

To a solution of 3.0 g (8.80 mmol) of the product of Step B in Example51 dissolved in 45 mL DMF was added 0.98 mL (8.80 mmol) of ethylbromoacetate and 5.73 g (17.6 mmol) of cesium carbonate. The reactionmixture was stirred at room temperature for 2 h then partitioned betweenEtOAc and water. The organic extracts were separated washed with water,10% aq. NaHSO₄, brine, dried (Na₂SO₄), filtered and evaporated. Theresidue was purified on a silica gel flash chromatography column elutedwith 0-20% EtOAc-hexane. Evaporation of the purified fractions anddrying in vacuo afforded the title compound.

Step B: Ethyl3-amino-6-(2-chlorophenyl)-5-(4-chlorophenyl)furo[2,3-b]pyridine-2-carboxylate

To a magnetically stirred solution of 2.69 g (6.30 mmol) of the productof Step A dissolved in 60 mL of DMF was slowly added 12.6 mL of a 1 Msolution of lithium bis(trimethylsilylamide) in THF at 0° C. Thereaction mixture was stirred at room temperature for 20 min thenpartitioned between EtOAc and 10% aq. NaHSO₄. The organic extracts wereseparated, washed with 10% aq. NaHSO₄, brine, dried (Na₂SO₄), filteredand evaporated. The residue was purified on a silica gel flashchromatography column eluted with 0-20% EtOAc-hexane. Evaporation of thepurified fractions and drying in vacuo afforded the title compound.HPLC/MS: 427.0 (M+1), 428.9 (M+3); R_(t)=4.03 min.

EXAMPLE 181

Ethyl6-(2-chlorophenyl)-5-(4-chlorophenyl)-3-[(trifluoroacetyl)amino]furo[2,3-b]pyridine-2-carboxylate

To a magnetically stirred solution of 0.70 g (1.64 mmol) of the productof Example 180 in 16 mL CH₂Cl₂ was sequentially added 0.23 mL (1.64mmol) of triethylamine and 0.23 mL (1.64 mmol) of trifluoroaceticanhydride at 0° C. The reaction mixture was stirred for 1-2 h andallowed to warn to room temperature. The reaction mixture was thenpartitioned between EtOAc and 10% aq. NaHSO₄ and the organic layer wasseparated. The organic extracts were washed with water and brine, dried(Na₂SO₄), filtered and evaporated. The residue was purified on a silicagel flash chromatography column eluted with 0-20% EtOAc-hexane.Evaporation of the purified fractions and drying in vacuo afforded thetitled compound. HPLC/MS: 523.0 (M+1), 524.8 (M+3); R_(t)=4.49 min.

EXAMPLE 182

6-(2-Chlorophenyl)-5-(4-chlorophenyl)-N,N-diethyl-3-[(trifluoroacetyl)amino]-furo[2,3-b]pyridine-2-carboxamide

To a magnetically stirred solution of 0.119 mL (1.15 mmol) oftriethylamine in 5 mL toluene was added 0.575 mL (1.15 mmol) of a 2.0 Msolution of trimethylaluminum in toluene at 0° C. The reaction mixturewas allowed to warm to room temperature and was stirred for 30 min. Asolution of 0.300 g (0.57 mmol) of the product of Example 181 in 1 mLCH₂Cl₂ was added to the reaction mixture and when the addition wascomplete the reaction mixture was heated at 60° C. for 2 h. The reactionmixture was allowed to cool again to room temperature and waspartitioned between EtOAc and 10% aq. NaHSO₄. The organic extracts werecombined, washed with water and brine, dried (Na₂SO₄), filtered andevaporated. The residue was purified on a silica gel flashchromatography column eluted with 0-30% EtOAc-hexane. Evaporation of thepurified fractions and drying in vacuo afforded the titled compound.HPLC/MS: 550.0 (M+1), 551.8 (M+3); R_(t)=4.74 min.

EXAMPLE 183

3-Amino-6-(2-chlorophenyl)-5-(4-chlorophenyl)-N,N-diethylfuro[2,3-b]pyridine-2-carboxamide

To a magnetically stirred solution of 0.273 g (0.50 mmol) of the productof Example 182 in 5 mL MeOH was added 0.343 g (0.248 mmol) of potassiumcarbonate and 0.5 mL water. The reaction mixture was stirred at 60° C.for 3 h then cooled to room temperature and partitioned between EtOAcand 10% aq. NaHSO₄. The organic extracts were separated, washed withwater and brine, dried (Na₂SO₄), filtered and evaporated. The residuewas purified on a silica gel flash chromatography column eluted with0-20% EtOAc-hexane. Evaporation of the purified fractions and drying invacuo afforded the titled compound. HPLC/MS: 453.9 (M+1), 455.8 (M+3);R_(t)=4.15 min.

EXAMPLES 184-195

Using the two-step amide synthesis and trifluoroacetamide hydrolysissequence described in Examples 182 and 183, the product of Example 181was converted to Examples of the title compound of general formula Iwherein R¹═CON^(d)R^(e) and R²=NH₂. These compounds were furthermodified using procedures described in reaction Schemes 6-8 and thepreceding Examples to afford the following compounds: HPLC/MS Ex. R² R⁴Name m/z; R_(t): 184

NEt₂ 3-(Acetylamino)-6-(2-Chlorophenyl)-5-(4-chlorophenyl)-N,N-diethylfuro[2,3- b]pyridine-2-carboxamide 496.0(M + 1), 498.0 (M + 3); 4.19 min 185

NMeEt 3-(Acetylamino)-6-(2-chlorophenyl)-5- (4-chlorophenyl)-N-ethyl-N-methylfuro[2,3-b]pyridine-2- carboxamide 482.0 (M + 1), 483.9 (M + 3);4.00 min 186 NH₂

6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(piperidin-1-ylcarbonyl)furo[2,3- b]pyridin-3-amine 466.1 (M + 1),467.9 (M + 3); 4.21 min 187

N-[6-(2-Chlorophenyl)-5-(4- chlorophenyl)-2-(piperidin-1-ylcarbony)furo[2,3-b]pyridin-3- yl]acetamide 508.1 (M + 1), 509.9 (M +3); 4.12 min 187

NEt₂ 6-(2-Chlorophenyl)-5-(4- chlorophenyl)-N,N-diethyl-3-(glycoloylamino)furo[2,3-b]pyridine-2- carboxamide 512.0 (M + 1), 513.8(M + 3); 3.98 min 188

NMe₂ 6-(2-Chlorophenyl)-5-(4- chlorophenyl)-3-(glycoloylamino)-N,N-dimethylfuro[2,3-b]pyridine-2- carboxamide 484.1 (M + 1), 486.1 (M +3); 3.81 min 189 NH₂

6-(2-Chlorophenyl)-5-(4- chlorophenyl)-2-(pyrrolidin-1-ylcarbonyl)furo[2,3-b]pyridin-3-amine 452.0 (M + 1), 454.0 (M + 3); 4.00min 190

1-[6-(2-chlorophenyl)-5-(4- chlorophenyl)-2-(pyrrolidin-1-ylcarbonyl)furo[2,3-b]pyridin-3- yl]pyrrolidine-2,5-dione 534.0 (M + 1),536.0 (M + 3); 3.77 min 191

1-[6-(2-chlorophenyl)-5-(4- chlorophenyl)-2-(pyrrolidin-1-ylcarbonyl)furo[2,3-b]pyridin-3-yl]-3- methylimmdazolidine-2,4-dione549.1 (M + 1), 551.1 (M + 3); 3.83 min 192

NEt₂ 6-(2-Chlorophenyl)-5-(4- chlorophenyl)-3-(2,4-dioxoimidazolidin-1-yl)-N,N- diethylfuro[2,3-b]pyridine-2- carboxamide537.0 (M + 1), 539.0 (M + 3); 3.73 min 193

NEt₂ 6-(2-Chlorophenyl)-5-(4- chlorophenyl)-N,N-diethyl-3-[(methylsulfonyl)amino]furo[2,3- b]pyridine-2-carboxamide 532.1 (M + 1),534.1 (M + 3); 4.18 min 194

NEt₂ 6-(2-Chlorophenyl)-5-(4- chlorophenyl)-N,N-diethyl-3-[(propylsulfonyl)amino]furo[2,3- b]pyridine-2-carboxamide 560.2 (M + 1),562.2 (M + 3); 4.42 min 195

NEt₂ 6-(2-Chlorophenyl)-5-(4- chlorophenyl)-3-(2,5-dioxopyrrolidin-1-yl)-N,N-diethylfuro[2,3-b]pyridine-2- carboxamide 536.1 (M + 1), 538.1(M + 3); 3.88 min

EXAMPLE 196

1-[6-(2-Chlorophenyl)-5-(4-chlorophenyl)-3-(1-methyl-1H-imidazol-2-yl)furo[2,3-b]pyridin-2-yl]-2,2-dimethylpropan-1-oneStep A:6-(2-chlorophenyl)-5-(4-chlorophenyl)-3-[(1-methyl-1H-imidazol-2-yl)carbonyl]pyridin-2(1H)-one

To a magnetically stirred solution of 0.233 mL (2.93 mmol) of2-methylimidazole in 6 mL THF at −78° was added 1.17 mL (2.93 mmol) of a2.5 M solution of n-butyllithium in hexane. The reaction was stirred at−60° C. for 1 h then a solution of 0.5 g (1.47 mmol) of the product ofStep B in Example 51 dissolved in 6 mL THF was added. The reactionmixture was stirred at room temperature for 4 h, then quenched byaddition of excess 2 N HCl. The mixture was adjusted to pH=7-8 with 1 NNaOH solution and extracted with CH₂Cl₂. The organic layers werecombined, dried (Na₂SO₄), filtered and evaporated. The residue was useddirectly in the next step without further purification.

Step B:1-({6-(2-Chlorophenyl)-5-(4-chlorophenyl)-3-[(1-methyl-1H-imidazol-2-yl)carbonyl]pyridin-2-yl}oxy)-3,3-dimethylbutan-2-one

To a solution of the product of Step A in 4 mL DMF was added 0.125 g(0.698 mmol) of 1-bromopinacolone and 0.455 g (1.39 mmol) of Cs₂CO₃. Thereaction mixture was stirred at room temperature for 1 h, thenpartitioned between EtOAc and saturated aqueous NaHCO₃ solution. Theorganic layer was separated, washed with aq. NaHCO₃, brine, dried(Na₂SO₄), filtered and evaporated. The residue was purified on a silicagel flash chromatography column eluted with 0-75% EtOAc-hexane.Evaporation of the purified fractions and drying in vacuo afforded thetitle compound.

Step C:1-[6-(2-Chlorophenyl)-5-(4-chlorophenyl)-3-(1-methyl-1H-imidazol-2-yl)furo[2,3-b]pyridin-2-yl]-2,2-dimethylpropan-1-one

A mixture of 0.094 g (0.18 mmol) of the product of Step B and 0.027 g(0.18 mmol) of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in 2 mL DMF wasplaced in a 10 mL reaction tube of a CEM Corporation Discover 300 Wattmicrowave reactor. The reaction vessel was sealed, placed in themicrowave reactor and heated at 150° C. for 5 min. After the reactionvessel had cooled again to room temperature, the reaction mixture waspartitioned between EtOAc and saturated aqueous NaHCO₃ solution. Theorganic layer was separated, washed with aq. NaHCO₃, brine, dried(Na₂SO₄), filtered and evaporated. The residue was purified on a silicagel flash chromatography column eluted with 0-75% EtOAc-hexane.Evaporation of the purified fractions and drying in vacuo afforded thetitle compound. HPLC/MS: 504.2 (M+1), 506.0 (M+3); R_(t)=3.39 min.

BIOLOGICAL EXAMPLE 1

Cannabinoid Receptor-1 (CB1) Binding Assay.

Binding affinity determination is based on recombinant human CB1receptor expressed in Chinese Hamster Ovary (CHO) cells (Felder et al,Mol. Pharmacol. 48: 443450, 1995). Total assay volume is 250 μL (240 μLCB1 receptor membrane solution plus 5 μL test compound solution plus 5μL [3H]CP-55940 solution). Final concentration of [3H]CP-55940 is 0.6nM. Binding buffer contains 50 mM Tris-HCl, pH7.4, 2.5 mM EDTA, SMMgCl₂, 0.5 mg/mL fatty acid free bovine serum albumin and proteaseinhibitors (Cat#P8340, from Sigma). To initiate the binding reaction, 5μL of radioligand solution is added, the mixture is incubated withgentle shaking on a shaker for 1.5 hours at 30° C. The binding isterminated by using 96-well harvester and filtering through GF/C filterpresoaked in 0.05% polyethylenimine. The bound radiolabel is quantitatedusing scintillation counter. Apparent binding affinities for variouscompounds are calculated from IC50 values (DeBlasi et al., TrendsPharmacol Sci 10: 227-229,1989).

The binding assay for CB2 receptor is done similarly with recombinanthuman CB2 receptor expressed in CHO cells.

CB1 antagonist/inverse agonist compounds of the present invention haveIC50s of less than 1 micromolar in the CB1 binding assay. Selective CB1antagonist/inverse agonist compounds have IC50s 100-fold greater in theCB2 binding assay than in the CB1 assay, and generally have IC50s ofgreater than one micromolar in the CB2 binding assay.

BIOLOGICAL EXAMPLE 2

Cannabinoid Receptor-1 (CB1) Functional Activity Assay.

The functional activation of CB1 receptor is based on recombinant humanCB1 receptor expressed in CHO cells (Felder et al, Mol. Pharmacol. 48:443-450, 1995). To determine the agonist activity or inverse agonistactivity of any test compound, 50 μL of CB1-CHO cell suspension aremixed with test compound and 70 uL assay buffer containing 0.34 mM3-isobutyl-1-methylxanthine and 5.1 μM of forskolin in 96-well plates.The assay buffer is comprised of Earle's Balanced Salt Solutionsupplemented with 5 mM MgCl₂, 1 mM glutamine, 10 mM HEPES, and 1 mg/mLbovine serum albumin. The mixture is incubated at room temperature for30 minutes, and terminated by adding 3011/well of 0.5M HCl. The totalintracellular cAMP level is quantitated using the New England NuclearFlashplate and cAMP radioimmunoassay kit.

To determine the antagonist activity of test compound, the reactionmixture also contains 0.5 nM of the agonist CP55940, and the reversal ofthe CP55940 effect is quantitated. Alternatively, a series of doseresponse curves for CP55940 is performed with increasing concentrationof the test compound in each of the dose response curves.

The functional assay for the CB2 receptor is done similarly withrecombinant human CB2 receptor expressed in CHO cells.

CB1 antagonist/inverse agonist compounds of the present inventiongenerally have EC50s of less than 1 micromolar in the CB1 functionalassay and selective CB1 antagonist/inverse agonists have generally haveEC50s of greater than 1 micromolar in the CB2 functional assay.

BIOLOGICAL EXAMPLE 3

Acute Food Intake Studies in Rats or Mice: General Procedure

Adult rats or mice are used in these studies. After at least 2 days ofacclimation to the vivarium conditions (controlled humidity andtemperature, lights on for 12 hours out of 24 hours) food is removedfrom rodent cages. Experimental compounds or their vehicles areadministered orally, intraperitoneally, subcutaneously or intravenouslybefore the return of a known amount of food to cage. The optimalinterval between dosing and food presentation is based on the half-lifeof the compound based on when brain concentrations of the compound isthe highest. Food remaining is measured at several intervals. Foodintake is calculated as grams of food eaten per gram of body weightwithin each time interval and the appetite-suppressant effect of thecompounds are compared to the effect of vehicle. In these experimentsmany strains of mouse or rat, and several standard rodent chows can beused.

BIOLOGICAL EXAMPLE 4

Chronic Weight Reduction Studies in Rats or Mice: General Procedure

Adult rats or mice are used in these studies. Upon or soon afterweaning, rats or mice are made obese due to exclusive access to dietscontaining fat and sucrose in higher proportions than in the controldiet. The rat strains commonly used include the Sprague Dawley bredthrough Charles River Laboratories. Although several mouse strains maybe used, c57B1/6 mice are more prone to obesity and hyperinsulinemiathan other strains. Common diets used to induce obesity include:Research Diets D12266B (32% fat) or D12451 (45% fat) and BioServ S3282(60% fat). The rodents ingest chow until they are significantly heavierand have a higher proportion of body fat than control diet rats, often 9weeks. The rodents receive injections (1 to 4 per day) or continuousinfusions of experimental compounds or their vehicles either orally,intraperitoneally, subcutaneously or intravenously. Food intake and bodyweights are measured daily or more frequently. Food intake is calculatedas grams of food eaten per gram of body weight within each time intervaland the appetite-suppressant and weight loss effects of the compoundsare compared to the effects of vehicle.

BIOLOGICAL EXAMPLE 5

Tail Suspension Test

The tail suspension test has been widely used for screeningantidepressant-like effects of compounds in mice (Steru et al., 1987),rats (Izumi et al, 1997) and gerbils (Varty et al., 2003). It is basedon the principle that helplessness takes place when the animal isexposed to a sustained aversive situation. Briefly, when the animal issuspended by its tail it exhibits several escape-oriented behaviorsintercalated with bouts of immobility that evolve with time intocomplete immobility. Pretreatment with a wide range of antidepressants,such as tricyclic compounds, monoamine uptake blockers, or serotoninreuptake inhibitors (SSRIs), significantly decrease duration ofimmobility throughout the test, while anxiolytics or antipsychotics donot (Wong et al., 2000; Oxenkrug 1999).

Subjects

Male mice are housed in a colony room maintained at constant temperature(22° C.) and humidity (30-70%), with food (Harlan Teklad Diet #7012, 5%fat; 3.75 kcal/gm) and water available ad libitum. For the behavioralexperiments, mice are group housed (10/cage) under a reversed light/darkcycle (lights on at 21:00 h, off at 09:00 h) and tests occurred between10:00 h and 14:00 h.

Drugs

The compounds of formula (1) are solubilized into 1% Tween80-salinesolution, addition of DMSO may be employed to increase solubility.Compounds are dosed intraperitonieally in a volume of 0.1 mL.

Tail Suspension Test

An automated tail-suspension apparatus (TSE Systems, Bad Homburg,Germany) with a tail hanger connected to a precision linear load cell isused. One centimeter of the mouse's tail is inserted into the tailhanger and secured with non-irritating adhesive tape. Mice are suspendedby the tail, at a height of 35 cm from the tabletop for 6 minutes.During this time the load cell records the mouse's movements andtransmits the information to a central computer, which then records therate of immobility within the course of the session, and calculatestotal duration of immobility.

Total duration of immobility is used as the dependent variable inone-way Analysis of Variance (ANOVA) on treatment.

While the invention has been described and illustrated with reference tocertain particular embodiments thereof, those skilled in the art willappreciate that various changes, modifications and substitutions can bemade therein without departing from the spirit and scope of theinvention. For example, effective dosages other than the particulardosages as set forth herein above may be applicable as a consequence ofvariations in the responsiveness of the mammal being treated for any ofthe indications for the compounds of the invention indicated above.Likewise, the specific pharmacological responses observed may varyaccording to and depending upon the particular active compound selectedor whether there are present pharmaceutical carriers, as well as thetype of formulation and mode of administration employed, and suchexpected variations or differences in the results are contemplated inaccordance with the objects and practices of the present invention. Itis intended, therefore, that the invention be defined by the scope ofthe claims which follow and that such claims be interpreted as broadlyas is reasonable.

1. A compound of structural formula I:

wherein: R¹ is selected from: (1) C₁₋₁₀alkyl, (2) C₂₋₁₀alkenyl, (3)C₂₋₁₀alkynyl, (4) —CN, (5) —COR⁴, (6) —S(O)_(m)R⁴, (7)—S(O)₂NH(CO)_(n)NR^(e), (8) cycloheteroalkyl, (9) aryl, and (10)heteroaryl, wherein alkyl, alkenyl, and alkynyl are optionallysubstituted with one, two, or three substituents independently selectedfrom R^(a), and cycloheteroalkyl, aryl and heteroaryl are optionallysubstituted with one, two, or three substituents independently selectedfrom R^(b); R² is selected from: (1) hydrogen, (2) —NR⁵R⁶, (3) —COR⁴,(4) C₁₋₆alkyl, (5) C₂₋₆ alkenyl, (6) C₂₋₆alkynyl, (7) aryl, (8)arylC₁₋₆alkyl-, (9) arylC₂₋₆alkenyl, (10) heteroaryl, (11)heteroarylC₁₋₆alkyl-, (12) heteroarylC₂₋₆alkenyl, (13) cycloheteroalkyl,(14) hydroxyl, and (15) OR^(g), wherein alkyl, alkenyl, and alkynyl areoptionally substituted with one, two, or three substituentsindependently selected from R^(a); and aryl and heteroaryl areoptionally substituted with one, two, or three substituentsindependently selected from R^(b), and cycloheteroalkyl is optionallysubstituted with one, two, three or four substituents independentlyselected from R^(b) and oxo; R³ is selected from: (1) hydrogen, (2)C₁₋₆alkyl, (3) C₁₋₆alkyloxy, (4) trifluoromethyl, (5) trifluoromethoxy,(6) halo, and (7) C₃₋₇cycloalkyl, wherein alkyl, and cycloalkyl areoptionally substituted with one, two, or three substituentsindependently selected from R^(a); R⁴ is selected from: (1) hydrogen,(2) C₁₋₁₀alkyl, (3) C₂₋₁₀alkenyl, (4) C₂₋₁₀alkynyl, (5) cycloalkyl, (6)cycloalkyl-C₁₋₁₀alkyl, (7) cycloheteroalkyl, (8) cycloheteroalkyl-C₁-oalkyl, (9) aryl, (10) heteroaryl, (11) aryl-C₁₋₁₀alkyl, (12)heteroaryl-C₁₋₁₀alkyl-, (13) —OR^(e), (14) —NR^(d)R^(e), (15)—NH(CO)OR^(e), and (16) —NR^(d)SO₂R^(e), wherein alkyl, alkenyl, alkynyland cycloalkyl are optionally substituted with one, two, three or foursubstituents independently selected from R^(a), and cycloheteroalkyl,aryl and heteroaryl are optionally substituted with one, two, three orfour substituents independently selected from R^(b); R⁵ and R⁶ are eachindependently selected from: (1) hydrogen, (2) C₁₋₁₀alkyl, (3) C₂₋₁₀alkenyl, (4) C₂₋₁₀alkynyl, (5) aryl, (6) heteroaryl, (7) cycloalkyl, (8)trifluoromethyl, (9) —C(O)—R^(c), (10) —CO₂R^(c), (11) —C(O)C(O)OR^(c),(12) —C(O)C(O)NR^(e)R^(f), (13) —S(O)_(m)R^(c), and (14)—C(O)N(R^(d))S(O)_(m)R^(c), wherein alkyl, alkenyl, alkynyl, andcycloalkyl may be optionally substituted with one or two R^(a)substituents, and aryl may be optionally substituted with one or twoR^(b) substituents, or R⁵ and R⁶ together form ═CH—N(R^(e))(R^(f)); Ar¹and Ar² are independently selected from: (1) aryl, (2) heteroaryl,wherein aryl and heteroaryl are optionally substituted with one, two,three or four substituents independently selected from R^(b); each R^(a)is independently selected from: (1) —OR^(e), (2) —NR^(d)S(O)_(m)R^(c),(3) —NO₂, (4) halogen, (5) —S(O)_(m)R^(c), (6) —SR^(e), (7)—S(O)₂OR^(e), (8) —S(O)_(m)NR^(e)R^(f), (9) —NR^(e)R^(f), (10)—O(CR^(e)R^(f))_(n)NR^(e)R^(f), (11) —C(O)R^(C), (12) —CO₂R^(c), (13)—CO₂(CR^(e)R^(f))_(n)CONR^(e)R^(f), (14) —OC(O)R^(c), (15) —CN, (16)—C(O)NR^(e)R^(f), (17) —NR^(d)C(O)R^(c), (18) —NR^(d)C(O)OR^(e), (19)—NR^(d)C(O)NR^(d)R^(e), (20) —CR^(d)(N—OR^(e)), (21) CF₃, (22) —OCF₃,(23) C₃₋₈cycloalkyl, and (24) cycloheteroalkyl; each R^(b) isindependently selected from: (1) R^(a), (2) C₁₋₁₀alkyl, (3) aryl, (4)arylC₁₋₄alkyl, (5) heteroaryl, and (6) heteroarylC₁₋₄alkyl, wherein aryland heteroaryl are unsubstituted or substituted with one, two or threesubstituents independently selected from R^(h); each R^(c) isindependently selected from: (1) hydrogen, (2) C₁₋₁₀alkyl, (3) C₂₋₁₀alkenyl, (4) C₂₋₁₀alkynyl, (5) C₁₋₈ perfluoroalkyl, (6) cycloalkyl, (7)cycloalkyl-C₁₋₁₀alkyl, (8) cycloheteroalkyl, (9)cycloheteroalkyl-C₁₋₁₀alkyl, (10) aryl, (11) heteroaryl, (12)aryl-C₁₋₁₀alkyl, (13) heteroaryl-C₁₋₁₀alkyl, and (14) —NR^(d)R^(d),wherein alkyl, cycloalkyl, cycloheteroalkyl, phenyl, and heteroaryl maybe substituted with one or two R^(h) substituents, and alkyl,cycloalkyl, cycloheteroalkyl may be substituted on a carbon or sulfuratom with one or two oxo substituents; each R^(d) is independentlyselected from hydrogen, C₁₋₁₀alkyl, C₁₋₁₀alkylcarbonyl-, arylsulfonyl,C₁₋₁₀alkylsulfonyl, wherein the alkyl and aryl groups may beunsubstituted or substituted with one, two or three substituentsindependently selected from R^(h) wherein the alkyl may be unsubstitutedor substituted with one, two or three substituents independentlyselected from R^(h); R^(e) and R^(f) are independently selected fromhydrogen, C₁₋₁₀alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀alkynyl, trifluoromethyl,cycloalkyl, cycloalkyl-C₁₋₁₀ alkyl, cycloheteroalkyl,cycloheteroalkyl-C₁₋₁₀ alkyl, aryl, heteroaryl, aryl-C₁₋₁₀ alkyl, andheteroaryl-C₁₋₁₀ alkyl at each occurrence; or when bonded to the sameatom, R^(e) and R^(f) together with the atom to which they are attachedform a ring of 5 to 7 members containing 0, 1, or 2 heteroatomsindependently selected from oxygen, sulfur and nitrogen; and each R^(e)and R^(f) may be unsubstituted or substituted on a carbon or nitrogenatom with one, two or three substituents selected from R^(h); R^(g) isselected from: (1) C₁₋₁₀alkyl, (2) C₁₋₁₀alkylcarbonyl-, (3) aryl, (4)arylcarbonyl, (5) C₁₋₁₀alkylsulfonyl, and (6) arylsulfonyl, wherein eachalkyl may be unsubstituted or substituted with one, two or three R^(a)substituents, and each aryl may be unsubstituted or substituted withone, two or three R^(b) substituents; each R^(h) is independentlyselected from: (1) halogen, (2) C₁₋₁₀alkyl, (3) C₃₋₈cycloalkyl, (4)cycloheteroalkyl, (5) aryl, (6) arylC₁₋₄alkyl, (7) heteroaryl, (8)heteroarylC₁₋₄alkyl, (9) —OR^(e), (10) —NR^(d)S(O)_(m)R^(e), (11)—S(O)_(m)R^(c), (12) —SR^(e), (13) —S(O)₂OR^(e), (14) —NR^(e)R^(e), (15)—O(CR^(d)R^(d))_(n)NR^(e)R^(f), (16) —C(O)R^(c), (17) —CO₂R^(e), (18)—CO₂(CR^(d)R^(d))_(n)CONR^(e)R^(f), (19) —OC(O)R^(e), (20) —CN, (21)—C(O)NR^(e)R^(f), (22) —NR^(d)C(O)R^(e), (23) —OC(O)NR^(e)R^(f), (24)—NR^(d)C(O)OR^(e), (25) —NR^(d)C(O)NR^(e)R^(f). (26) CF₃, and (27)—OCF₃, m is selected from 1 and 2; and n is selected from 1, 2, and 3;or a pharmaceutically acceptable salt thereof.
 2. A compound ofstructural formula I:

wherein; R¹ is selected from: (1) C₁₋₁₀alkyl, (2) C₂₋₁₀alkenyl, (3)C₂₋₁₀alkynyl, (4) —CN, (5) —COR⁴, (6) —S(O)_(m)R⁴, (7)—S(O)₂NH(CO)_(n)NR^(e), (8) aryl, and (9) heteroaryl, wherein alkyl,alkenyl, and alkynyl are optionally substituted with one, two, or threesubstituents independently selected from R^(a), and aryl and heteroarylare optionally substituted with one, two, or three substituentsindependently selected from R^(b); R² is selected from: (1) hydrogen,(2) —NR⁵R⁶, (3) —COR⁴, (4) C₁₋₆alkyl, (5) C₂₋₆ alkenyl, (6) C₂₋₆alkynyl,(7) aryl, (8) heteroaryl, (9) cycloheteroalkyl, (10) hydroxyl, and (11)OR⁹, wherein alkyl, alkenyl, and alkynyl are optionally substituted withone, two, or three substituents independently selected from R^(a); andaryl, heteroaryl, and cycloheteroalkyl are optionally substituted withone, two, or three substituents independently selected from R^(b); R³ isselected from: (1) hydrogen, (2) C₁₋₆alkyl, (3) C₁₋₆alkyloxy, (4)trifluoromethyl, (5) trifluoromethoxy, (6) halo, and (7) C₃₋₇cycloalkyl,wherein alkyl, and cycloalkyl are optionally substituted with one, two,or three substituents independently selected from R^(a); R⁴ is selectedfrom: (1) hydrogen, (2) C₁₋₁₀alkyl, (3) C₂₋₁₀alkenyl, (4) C₂₋₁₀alkynyl,(5) cycloalkyl, (6) cycloalkyl-C₁₋₁₀alkyl, (7) cycloheteroalkyl, (8)cycloheteroalkyl-C₁₋₁₀ alkyl, (9) aryl, (10) heteroaryl, (11)aryl-C₁₋₁₀alkyl-, (12) heteroaryl-C₁₋₁₀alkyl-, (13) —OR^(e), (14)—NR^(d)R^(e), (15) —NH(CO)OR^(e), and (16) —NR^(d)SO₂R^(e), whereinalkyl, alkenyl, alkynyl and cycloalkyl are optionally substituted withone, two, three or four substituents independently selected from R^(a),and cycloheteroalkyl, aryl and heteroaryl are optionally substitutedwith one, two, three or four substituents independently selected fromR^(b); R⁵ and R⁶ are each independently selected from: (1) hydrogen, (2)C₁₋₁₀alkyl, (3) C₂₋₁₀ alkenyl, (4) C₂₋₁₀alkynyl, (5) aryl, (6)cycloalkyl, (7) trifluoromethyl, (8) —C(O)—R^(c), (9) —CO₂R^(c), and(10) —S(O)_(m)R^(c), wherein alkyl, alkenyl, alkynyl, and cycloalkyl maybe optionally substituted with one or two R^(a) substituents, and arylmay be optionally substituted with one or two R^(b) substituents; Ar¹and Ar² are independently selected from: (1) aryl, (2) heteroaryl,wherein aryl and heteroaryl are optionally substituted with one, two,three or four substituents independently selected from R^(b); each R^(a)is independently selected from: (1) —OR^(e), (2) —NR^(d)S(O)_(m)R^(c),(3) —NO₂, (4) halogen, (5) —S(O)_(m)R^(c), (6) —SR^(e), (7)—S(O)₂OR^(e), (8) —S(O)_(m)NR^(e)R^(f), (9) —NR^(e)R^(f), (10)—O(CR^(e)R^(f))_(n)NR^(e)R^(f), (11) —C(O)R^(c), (12) —CO₂R^(c), (13)—CO₂(CR^(e)R^(f))_(n)CONR^(e)R^(f), (14) —OC(O)R^(c), (15) —CN, (16)—C(O)NR^(e)R^(f), (17) —NR^(d)C(O)R^(c), (18) —NR^(d)C(O)OR^(e), (19)—NR^(d)C(O)NR^(d)R^(e), (20) —CR^(d)(N—OR^(e)), (21) CF₃, (22) —OCF₃,(23) C₃₋₈cycloalkyl, and (24) cycloheteroalkyl; each R^(b) isindependently selected from: (1) R^(a), (2) C₁₋₁₀alkyl, (3) aryl, (4)arylC₁₋₁₄alkyl, (5) heteroaryl, and (6) heteroarylC₁₋₄alkyl; each R^(c)is independently selected from: (1) hydrogen, (2) C₁₋₁₀alkyl, (3) C₂₋₁₀alkenyl, (4) C₂₋₁₀alkynyl, (5) trifluoromethyl, (6) cycloalkyl, (7)cycloalkyl-C₁₋₁₀alkyl, (8) cycloheteroalkyl, (9)cycloheteroalkyl-C₁₋₁₀alkyl, (10) aryl, (11) heteroaryl, (12)aryl-C₁₋₁₀alkyl, (13) heteroaryl-C₁₋₁₀alkyl, and (14) —NR^(d)R^(d),wherein alkyl, cycloalkyl, cycloheteroalkyl, phenyl, and heteroaryl maybe substituted with one or two R^(h) substituents; each R^(d) isindependently selected from hydrogen and C₁₋₁₀alkyl; R^(e) and R^(f) areindependently selected from hydrogen, C₁₋₁₀alkyl, C₂₋₁₀ alkenyl,C₂₋₁₀alkynyl, trifluoromethyl, cycloalkyl, cycloalkyl-C₁₋₁₀ alkyl,cycloheteroalkyl, cycloheteroalkyl-C₁₋₁₀ alkyl, aryl, heteroaryl,aryl-C₁₋₁₀ alkyl, and heteroaryl-C₁₋₁₀ alkyl at each occurrence; or whenbonded to the same atom, R^(e) and R^(f) together with the atom to whichthey are attached form a ring of 5 to 7 members containing 0, 1, or 2heteroatoms independently selected from oxygen, sulfur and nitrogen; andeach R^(e) and R^(f) may be unsubstituted or substituted on a carbon ornitrogen atom with one, two or three substituents selected from R^(h);R^(g) is selected from: (1) C₁₋₁₀alkyl, (2) C₁₋₁₀alkylcarbonyl-, (3)aryl, (4) arylcarbonyl, (5) C₁₋₁₀alkylsulfonyl, and (6) arylsulfonyl,wherein each alkyl may be unsubstituted or substituted with one, two orthree R^(a) substituents, and each aryl may be unsubstituted orsubstituted with one, two or three R^(b) substituents; each R^(h) isindependently selected from: (1) halogen, (2) C₁₋₁₀alkyl, (3)C₃₋₈cycloalkyl, (4) cycloheteroalkyl, (5) aryl, (6) arylC₁₋₄alkyl, (7)heteroaryl, (8) heteroarylC₁₋₄alkyl, (9) —OR^(e), (10)—NR^(d)S(O)_(m)R^(e), (11) —S(O)_(m)R^(c), (12) —SR^(e), (13)—S(O)₂OR^(e), (14) —NR^(e)R^(e), (15) —O(CR^(d)R^(d))_(n)NR^(e)R^(f),(16) —C(O)R^(c), (17) —CO₂R^(e), (18)—CO₂(CR^(d)R^(d))_(n)CONR^(e)R^(f), (19) —OC(O)R^(e), (20) —CN, (21)—C(O)NR^(e)R^(f), (22) —NR^(d)C(O)R^(e), (23) —OC(O)NR^(e)R^(f), (24)—NR^(d)C(O)OR^(e), (25) —NR^(d)C(O)NR^(e)R^(f), (26) CF₃, and (27)—OCF₃, m is selected from 1 and 2; and n is selected from 1, 2, and 3;or a pharmaceutically acceptable salt thereof.
 3. The compound accordingto claim 2, wherein R³ is selected from: (1) hydrogen, (2) methyl, (3)ethyl, (4) propyl, (5) t-butyl, (6) methoxy, (7) ethyloxy, (8)propyloxy, (9) t-butyloxy, (10) trifluoromethyloxy, (11)trifluoromethyl, (12) halo, and (13) cyclopropyl, wherein the alkyl andcyclopropyl moieties are optionally substituted with one or twosubstituents independently selected from: halo, trifluoromethyl,methoxy, ethyloxy, methoxycarbonyl, and carboxyl; and pharmaceuticallyacceptable salts thereof.
 4. The compound according to claim 3, whereinAr¹ and Ar² are each independently selected from: (1) phenyl, and (2)pyridyl, wherein phenyl and pyridyl are optionally substituted with oneor two R^(b) substituents; and pharmaceutically acceptable saltsthereof.
 5. The compound according to claim 4, wherein Ar¹ and Ar² areeach independently selected from: (1) phenyl, and (2) pyridyl; whereinphenyl and pyridyl are optionally substituted with one or two halogen,methyl, trifluoromethyl or cyano substituents, and pharmaceuticallyacceptable salts thereof.
 6. The compound according to claim 4, whereinR¹ is selected from: (1) C₁₋₆alkyl, (2) cyano, (3) C₁₋₁₆alkylcarbonyl,(4) cycloalkylcarbonyl, (5) cycloheteroalkylcarbonyl, (6)phenylcarbonyl, (7) heteroarylcarbonyl, (8) C₁₋₆alkyloxycarbonyl, (9)trifluoromethyloxycarbonyl, (10) cycloalkyloxycarbonyl, (11) —CON(CH₃)₂,(12) —CONH(CH₃), (13) —CONH(CF₃), (14) —CON(CH₂CH₃)₂, (15)—CONH(CH₂CH₃), (16) —CONH(cyclopropyl), (17) —CON(cyclopropyl)₂, (18)C₁₋₆alkylsulfonyl-, (19) cycloalkylsulfonyl-, (20)cycloheteroalkylsulfonyl-, (21) phenylsulfonyl-, (22)heteroarylsulfonyl-, (23) C₁₋₆alkyloxysulfonyl-, (24)trifluoromethyloxysulfonyl-, (25) cycloalkyloxysulfonyl-, (26)cycloheteroalkyloxysulfonyl-, (27) phenyloxysulfonyl-, (28)heteroaryloxysulfonyl-, (29) —S(O)₂NR^(d)R^(e), (30)—S(O)₂NH(CO)C₁₋₆alkyl, and (31) —S(O)₂NH(CO)aryl; wherein alkyl, andcycloalkyl are optionally substituted with one, or two substituentsindependently selected from R^(a), and cycloheteroalkyl, aryl, andheteroaryl are optionally substituted with one or two substituentsindependently selected from R^(b); each R^(a) is independently selectedfrom: (1) —OR^(e), (2) halogen, (3) —S(O)₂R^(c), (4) —SR^(e), (5)—S(O)₂OR^(e), (6) —S(O)₂NR^(e)R^(f), (7) —NR^(e)R^(f), (8) —C(O)R^(c),(9) —CO₂R^(c), (10) —CN, (11) —CH(N—OR^(e)), (12) CF₃, (13) —OCF₃, (14)C₃₋₈cycloalkyl, and (15) cycloheteroalkyl; each R^(b) is independentlyselected from: (1) —OR^(e), (2) halogen, (3) —S(O)₂R^(c), (4) —SH, (5)—SCH₃, (6) —NR^(e)R^(f), (7) —C(O)R^(c), (8) —CO₂R^(c), (9) —CN, (10)CF₃, (11) —OCF₃, (12) C₃₋₈cycloalkyl, (13) cycloheteroalkyl; (14)C₁₋₄alkyl, (15) phenyl, (16) benzyl, (17) heteroaryl, and (18)heteroarylmethyl; each R^(c) is independently selected from: (1)hydrogen, (2) C₁₋₆alkyl, (3) trifluoromethyl, (4) cycloalkyl, (5)cycloheteroalkyl, (6) phenyl, (7) heteroaryl, and (8) —NR^(d)R^(d),wherein alkyl, cycloalkyl, cycloheteroalkyl, phenyl, and heteroaryl maybe substituted with one or two R^(h) substituents; each R^(d) isindependently selected from: (1) hydrogen, and (2) C₁₋₆ alkyl; eachR^(e) is independently selected from: hydrogen, C₁₋₄alkyl,trifluoromethyl, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, pyridyl,pyridinyl, pyrazinyl, pyridazinyl, benzyl, and pyridylmethyl,pyrazinylmethyl, and pyridazinylmethyl at each occurrence, eitherunsubstituted or substituted on a carbon or nitrogen atom with one ortwo substituents selected from R^(h); each R^(f) is independentlyselected from: hydrogen, C₁₋₄alkyl, trifluoromethyl, cyclopropyl,cyclopentyl, cyclohexyl, cycloheteroalkyl, phenyl, pyridyl, pyridinyl,pyrazinyl, pyridazinyl, benzyl, pyridylmethyl, pyridinylmethyl,pyrazinylmethyl, and pyridazinylmethyl at each occurrence, eitherunsubstituted or substituted on a carbon or a cycloheteroalkyl nitrogenatom with one or two substituents selected from R^(h); or R^(e) andR^(f), together with the atom to which they are attached form a ringselected from: pyrrolidinyl, piperidinyl, morpholinyl,1-thia-4-azacyclohexyl, azacycloheptyl, unsubstituted or substituted ona carbon or nitrogen atom with one or two or three substituents selectedfrom R^(h); R^(g) is selected from: (1) C₁₋₆alkyl, (2) methylcarbonyl-,(3) phenyl, (4) phenylcarbonyl, (5) methylsulfonyl, and (6)phenylsulfonyl, wherein each alkyl may be unsubstituted or substitutedwith an R^(a) substituent, and each phenyl may be unsubstituted orsubstituted with one or two R^(b) substituents; each R^(h) isindependently selected from: (1) halogen, (2) hydroxy, (3) methyl, (4)methoxy, (5) methylthio-, (6) —CN, (7) —CF₃, and (8) —OCF₃; andpharmaceutically acceptable salts thereof.
 7. The compound according toclaim 6, wherein R² is selected from: (1) hydrogen, (2) —NR⁵R⁶, (3)—COR⁴, (4) C₁₋₆alkyl, unsubstituted or substituted with one or two R^(a)substituents, (5) phenyl, unsubstituted or substituted with one or twoR^(b) substituents, (6) heteroaryl selected from: pyridinyl,benzimidazolyl, imidazolyl, oxazolidinyl, pyrimidyl, pyridazinyl,pyrazinyl, triazolyl, and benzotriazolyl, wherein the heteroaryl may beunsubstituted or substituted on one or two carbon atoms with R^(b), (7)a nitrogen-linked 5 to 7 membered ring, optionally containing one otherheteroatom selected from nitrogen, sulfur and oxygen, unsubstituted orsubstituted on nitrogen or carbon with an R^(b) substituent, (8)hydroxyl, and (9) Or^(g), and pharmaceutically acceptable salts thereof.8. The compound according to claim 7, wherein: R⁴ is selected from: (1)hydrogen, (2) C₁₋₆alkyl, (3) cycloalkyl, (4) cycloheteroalkyl, (5)phenyl, (6) heteroaryl, (7) aryl-C₁₋₃alkyl, (8) heteroaryl-C₁₋₃alkyl-,(9) —OR^(e), (10) —NR^(d)R^(e), (11) —NH(CO)OR^(e), and (12)—NHSO₂R^(e), wherein alkyl and cycloalkyl are optionally substitutedwith one, or two substituents independently selected from R^(a), andcycloheteroalkyl, aryl and heteroaryl are optionally substituted withone or two substituents independently selected from R^(b); R⁵ isselected from: (1) hydrogen, (2) C₁₋₄alkyl, (3) phenyl, (4) cyclopropyl,(5) cyclopentyl, (6) cyclohexyl, (7) trifluoromethyl, (8)methylcarbonyl-, (9) methoxycarbonyl-, (10) hydroxycarbonyl-, and (11)—S(O)₂CH₃; R⁶ is selected from: (1) hydrogen, (2) C₁₋₆alkyl, (3)trifluoromethyl, (4) phenyl, (5) cycloalkyl, (6) —C(O)—R^(c), (7)—CO₂R^(c), and (8) —S(O)₂R^(c), wherein phenyl may be substituted withone or two R^(b) substituents; and pharmaceutically acceptable saltsthereof.
 9. The compound according to claim 1, wherein: R¹ is selectedfrom: (1) C₁₋₁₀alkyl, (2) —CN, (3) —COR⁴, (4) —S(O)₂R⁴, (5)cycloheteroalkyl, (6) aryl, and (7) heteroaryl, wherein alkyl isoptionally substituted with one, two, or three substituentsindependently selected from R^(a), and cycloheteroalkyl, aryl andheteroaryl are optionally substituted with one, two, or threesubstituents independently selected from R^(b); R² is selected from: (1)hydrogen, (2) —NR⁵R⁶, (3) —COR⁴, (4) C₁₋₆alkyl, unsubstituted orsubstituted with one or two R^(a) substituents, (5) phenyl,unsubstituted or substituted with one or two R^(b) substituents, (6)phenylC₁₋₃alkyl-, (7) heteroaryl, (8) heteroarylC₁₋₁₃alkyl-, (9) anitrogen-linked 5 to 7 membered ring, optionally containing one otherheteroatom selected from nitrogen, sulfur and oxygen, unsubstituted orsubstituted on nitrogen, sulfur or carbon with one, two, three or foursubstituents selected from R^(b) and oxo, (10) hydroxyl, and (11)OR^(g); wherein alkyl is optionally substituted with one or twosubstituents independently selected from R^(a), and phenyl is optionallysubstituted with one or two substituents independently selected fromR^(b), and heteroaryl is selected from: pyridinyl, benzimidazolyl,imidazolyl, oxazolidinyl, pyrimidyl, pyridazinyl, pyrazinyl, triazolyl,and benzotriazolyl, wherein the heteroaryl may be unsubstituted orsubstituted on one or two carbon atoms with R^(b); R³ is hydrogen; R⁴ isselected from: (1) methyl, (2) ethyl, unsubstituted or substituted withone or two substituents selected from halo, OR^(e), and —OC(O)R^(c), (3)isopropyl, unsubstituted or substituted with one or two substituentsfrom halo, OR^(e), and —OC(O)R^(c), (4) n-propyl, unsubstituted orsubstituted with one or two substituents selected from halo, OR^(e), and—OC(O)R^(c), (5) t-butyl, unsubstituted or substituted with one or twosubstituents selected from from halo, OR^(e), and —OC(O)R^(c), (6) C₃₋₆cycloalkyl, (7) phenyl, unsubstituted or substituted with one or twosubstituents selected from halo, methyl, trifluoromethyl, methoxy,methoxycarbonyl, —NHC(O)R^(c), and carboxyl, (8) phenyl-C₁₋₁₃alkyl,wherein the alkyl moiety is unsubsituted or substituted with asubstituent selected from: halo, methyl, trifluoromethyl, methoxy,methoxy carbonyl, carboxyl, and —NHC(O)R^(c), (9) heteroaryl selectedfrom furanyl, pyridyl and imidazolyl, unsubstituted or substituted withone or two substituents selected from halo, methyl, trifluoromethyl,methoxy, methoxycarbonyl, and carboxyl, (10) cycloheteroalkyl, selectedfrom morpholinyl, piperidinyl, pyrrolidinyl, piperazinyl,imidazolidinyl, azetidinyl, azabicyclo[3.1.0]hexyl, andisothiazolidinyl, unsubstituted or substituted with methyl or —CO₂R^(c),(11) methoxy, (12) ethyloxy, (13) t-butyloxy, (14) isopropyloxy, and(15) —NR^(d)R^(e); R⁵ is selected from: (1) hydrogen, (2) C₁₋₄alkyl, (3)C₂₋₄alkenyl, (4) phenyl, (5) cycloalkyl, (6) trifluoromethyl, (7)methylcarbonyl-, (8) methoxycarbonyl-, (9) t-butyloxycarbonyl, (10)hydroxycarbonyl-, (11) —C(O)C(O)OR^(c), (12) —C(O)C(O)NR^(e)R^(f), (13)—S(O)₂R^(c), and (14) —C(O)N(R^(d))S(O)_(m)R^(c), wherein alkyl,alkenyl, and cycloalkyl may optionally be substituted with one or twoR^(a) substituents, and phenyl may be substituted with one or two R^(b)substituents; R⁶ is selected from: (1) hydrogen, (2) C₁₋₆alkyl, (3)C₂₋₆alkenyl, (4) trifluoromethyl, (5) phenyl, (6) heteroaryl, (7)cycloalkyl, (8) —C(O)—R^(c), (9) —CO₂R^(c), (10) —C(O)C(O)OR^(c), (11)—C(O)C(O)NR^(e)R^(f), (12) —S(O)₂R^(c), and (13)—C(O)N(R^(d))S(O)_(m)R^(c), wherein alkyl, alkenyl, alkynyl, andcycloalkyl may be optionally substituted with one or two R^(a)substituents, and aryl may be optionally substituted with one or twoR^(b) substituents; or R⁵ and R⁶ together form ═CH—N(R^(e))(R^(f)); Ar¹is 4-chlorophenyl; Ar² is 2,4-dichlorophenyl or 2-chlorophenyl; eachR^(a) is independently selected from: (1) —OR^(e), (2)—NR^(d)S(O)_(m)R^(c), (3) —NO₂, (4) halogen, (5) —S(O)_(m)R^(c), (6)—SR^(e), (7) —S(O)₂OR^(e), (8) —S(O)_(m)NR^(e)R^(f), (9) —NR^(e)R^(f),(10) —O(CR^(e)R^(f))_(n)NR^(e)R^(f), (11) —C(O)R^(c), (12) —CO₂R^(c),(13) —CO₂(CR^(e)R^(f))_(n)CONR^(e)R^(f), (14) —OC(O)R^(c), (15) —CN,(16) —C(O)NR^(e)R^(f), (17) —NR^(d)C(O)R^(c), (18) —NR^(d)C(O)OR^(e),(19) —NR^(d)C(O)NR^(d)R^(e), (20) —CR^(d)(N—OR^(e)), (21) CF₃, (22)—OCF₃, (23) C₃₋₈cycloalkyl, and (24) cycloheteroalkyl; each R^(b) isindependently selected from: (1) R^(a), (2) C₁₋₁₀alkyl, (3) aryl, (4)arylC₁₋₄alkyl, (5) heteroaryl, and (6) heteroarylC₁₋₄alkyl, wherein eacharyl and heteroaryl is unsubstituted or substituted with one or twoR^(h) substituents; each R^(c) is independently selected from: (1)hydrogen, (2) C₁₋₆alkyl, (3) C₁₋₇ perfluoromethyl, (4) cycloalkyl, (5)cycloheteroalkyl, (6) cycloheteroalkylC₁₋₃ alkyl, (7) phenyl, (8)phenylC₁₋₃ alkyl, (9) heteroaryl, (10) heteroarylC₁₋₃ alkyl, and (11)—NR^(d)R^(d); wherein alkyl, cycloalkyl, cycloheteroalkyl, phenyl, andheteroaryl may be substituted with an R^(h) substituent and alkyl,cycloalkyl, cycloheteroalkyl may be substituted on a carbon or sulfuratom with one or two oxo substituents, each R^(d) is independentlyselected from each R^(d) is independently selected from hydrogen,C₁₋₁₀alkyl, C₁₋₁₀alkylsulfonyl, arylsulfonyl and C₁₋₁₀alkylcarbonyl-,wherein the alkyl may be unsubstituted or substituted with one, two orthree substituents independently selected from R^(h); R^(e) and R^(f)are independently selected from hydrogen, C₁₋₁₀alkyl, C₂₋₁₀ alkenyl,C₂₋₁₀alkynyl, trifluoromethyl, cycloalkyl, cycloalkyl-C₁₋₁₀ alkyl,cycloheteroalkyl, cycloheteroalkyl-C₁₋₁₀ alkyl, aryl, heteroaryl,aryl-C₁₋₁₀ alkyl, and heteroaryl-C₁₋₁₀ alkyl at each occurrence; or whenbonded to the same atom, R^(e) and R^(f) together with the atom to whichthey are attached form a ring of 5 to 7 members containing 0, 1, or 2heteroatoms independently selected from oxygen, sulfur and nitrogen; andeach R^(e) and R^(f) may be unsubstituted or substituted on a carbon ornitrogen atom with one, two or three substituents selected from R^(h);R^(g) is selected from: (1) C₁₋₁₀alkyl, (2) C₁₋₁₀alkylcarbonyl-, (3)aryl, (4) arylcarbonyl, (5) C₁₋₁₀alkylsulfonyl, and (6) arylsulfonyl,wherein each alkyl may be unsubstituted or substituted with one, two orthree R^(a) substituents, and each aryl may be unsubstituted orsubstituted with one, two or three R^(b) substituents; each R^(h) isindependently selected from: (1) halogen, (2) C₁₋₁₀alkyl, (3)C₃₋₈cycloalkyl, (4) cycloheteroalkyl, (5) aryl, (6) arylC₁₋₄alkyl, (7)heteroaryl, (8) heteroarylC₁₋₄alkyl, (9) —OR^(e), (10)—NR^(d)S(O)_(m)R^(e), (11) —S(O)_(m)R^(c), (12) —SR^(e), (13)—S(O)₂OR^(e), (14) —NR^(e)R^(e), (15) —O(CR^(d)R^(d))_(n)NR^(e)R^(f),(16) —C(O)R^(c), (17) —CO₂R^(e), (18)—CO₂(CR^(d)R^(d))_(n)CONR^(e)R^(f), (19) —OC(O)R^(e), (20) —CN, (21)—C(O)NR^(e)R^(f), (22) —NR^(d)C(O)R^(e), (23) —OC(O)NR^(e)R^(f), (24)—NR^(d)C(O)OR^(e), (25) —NR^(d)C(O)NR^(e)R^(f), and (26) CF₃, andpharmaceutically acceptable salts thereof.
 10. The compound according toclaim 2, selected from: (1)[3-amino-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)furo[2,3-b]pyridin-2-yl](phenyl)methanone,(2)N-[2-benzoyl-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)furo[2,3-b]pyridin-3-yl]acetamide,(3)1-[3-amino-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)furo[2,3-b]pyridin-2-yl]ethanone,(4)N-[2-acetyl-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)furo[2,3-b]pyridin-3-yl]acetamide,(5)N-[2-acetyl-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)furo[2,3-b]pyridin-3-yl]-N-(methylsulfonyl)methanesulfonamide,(6) ethyl3-amino-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)furo[2,3-b]pyridine-2-carboxylate,(7) ethyl3-(acetylamino)-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)furo[2,3-b]pyridine-2-carboxylate,(8)N-[5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)-2-(piperidin-1-ylcarbonyl)furo[2,3-b]pyridin-3-yl]acetamide,(9)N-{5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)-2-[(4-methylpiperazin-1-yl)carbonyl]furo[2,3-b]pyridin-3-yl]acetamide,(10)3-(acetylamino)-5-(4-chlorophenyl)-N-cyclopropyl-6-(2,4-dichlorophenyl)furo[2,3-b]pyridine-2-carboxamide,(11)N-[5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)-2-(pyrrolidin-1-ylcarbonyl)furo[2,3-b]pyridin-3-yl]acetamide,(12)1-[3-amino-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)furo[2,3-b]pyridin-2-yl]-2,2-dimethylpropan-1-one,(13)N-[5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)-2-(2,2-dimethylpropanoyl)furo[2,3-b]pyridin-3-yl]acetamide,(14)[3-amino-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)furo[2,3-b]pyridin-2-yl](pyridin-3-yl)methanone,(15)[3-amino-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)furo[2,3-b]pyridin-2-yl](3,4-difluorophenyl)methanone,(16)[3-amino-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)furo[2,3-b]pyridin-2-yl](3,4-difluorophenyl)methanone,(17)N-[5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)-2-(pyridin-3-ylcarbonyl)furo[2,3-b]pyridin-3-yl]-2,2-dimethylpropanamide,(18) methyl5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)-2-(pyridin-3-ylcarbonyl)furo[2,3-b]pyridin-3-ylcarbamate, (19)N-[5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)-2-(2,2-dimethylpropanoyl)furo[2,3-b]pyridin-3-yl]sulfamide, (20)N-[5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)-2-(2,2-dimethylpropanoyl)furo[2,3-b]pyridin-3-yl]methanesulfonamide, (21)N-[2-(2-azabicyclo[2.2.2]oct-2-ylcarbonyl)-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)furo[2,3-b]pyridin-3-yl]acetamide,(22)N′-[5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)-2-(pyridin-3-ylcarbonyl)furo[2,3-b]pyridin-3-yl]-N,N-dimethylurea,(23)N-[5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)-2-(pyridin-3-ylcarbonyl)furo[2,3-b]pyridin-3-yl]-2,2,2-trifluoroacetamide,(24)1-[3-amino-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)furo[2,3-b]pyridin-2-yl]propan-1-one,(25)N-[5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)-2-(2,2-dimethylpropanoyl)furo[2,3-b]pyridin-3-yl]-2,2,2-trifluoroacetamide,(26)1-[5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)-3-(methylamino)furo[2,3-b]pyridin-2-yl]-2,2-dimethylpropan-1-one,(27)1-[5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)-3-(dimethylamino)furo[2,3-b]pyridin-2-yl]-2,2-dimethylpropan-1-one,(28)[5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)-3-(dimethylamino)furo[2,3-b]pyridin-2-yl](pyridin-3-yl)methanone,(29)3-amino-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)furo[2,3-b]pyridine-2-carbonitrile,(30)N-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2-hydroxy-2-methylpropanoyl)furo[2,3-b]pyridin-3-yl]-2-hydroxyacetamide, (31)N-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2-hydroxy-2-methylpropanoyl)furo[2,3-b]pyridin-3-yl]acetamide, (32)N-[5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)-2-(2-hydroxy-2-methylpropanoyl)furo[2,3-b]pyridin-3-yl]-2-hydroxyacetamide, andpharmaceutically acceptable salts thereof.
 11. The compound according toclaim 2, selected from: (1)[3-amino-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)furo[2,3-b]pyridin-2-yl](phenyl)methanone,(2)N-[2-benzoyl-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)furo[2,3-b]pyridin-3-yl]acetamide,(3)1-[3-amino-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)furo[2,3-b]pyridin-2-yl]ethanone,(4)N-[2-acetyl-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)furo[2,3-b]pyridin-3-yl]acetamide,(5)N-[2-acetyl-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)furo[2,3-b]pyridin-3-yl]-N-(methylsulfonyl)methanesulfonamide,(6) ethyl 3-amino-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)furo[2,3-b]pyridine-2-carboxylate, (7) ethyl3-(acetylamino)-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)furo[2,3-b]pyridine-2-carboxylate,(8)N-[5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)-2-(piperidin-1-ylcarbonyl)furo[2,3-b]pyridin-3-yl]acetamide,(9)N-{5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)-2-[(4-methylpiperazin-1-yl)carbonyl]furo[2,3-b]pyridin-3-yl}acetamide,(10)3-(acetylamino)-5-(4-chlorophenyl)-N-cyclopropyl-6-(2,4-dichlorophenyl)furo[2,3-b]pyridine-2-carboxamide,(11)N-[5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)-2-(pyrrolidin-1-ylcarbonyl)furo[2,3-b]pyridin-3-yl]acetamide,(12)1-[3-amino-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)furo[2,3-b]pyridin-2-yl]-2,2-dimethylpropan-1-one,(13)N-[5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)-2-(2,2-dimethylpropanoyl)furo[2,3-b]pyridin-3-yl]acetamide,(14)[3-amino-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)furo[2,3-b]pyridin-2-yl](pyridin-3-yl)methanone,(15)[3-amino-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)furo[2,3-b]pyridin-2-yl](3,4-difluorophenyl)methanone,(16)[3-amino-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)furo[2,3-b]pyridin-2-yl](3,4-difluorophenyl)methanone,(17)N-[5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)-2-(pyridin-3-ylcarbonyl)furo[2,3-b]pyridin-3-yl]-2,2-dimethylpropanamide,(18) methyl5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)-2-(pyridin-3-ylcarbonyl)furo[2,3-b]pyridin-3-ylcarbamate, (19)N-[5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)-2-(2,2-dimethylpropanoyl)furo[2,3-b]pyridin-3-yl]sulfamide, (20)N-[5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)-2-(2,2-dimethylpropanoyl)furo[2,3-b]pyridin-3-yl]methanesulfonamide, (21)N-[2-(2-azabicyclo[2.2.2]oct-2-ylcarbonyl)-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)furo[2,3-b]pyridin-3-yl]acetamide,(22)N′-[5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)-2-(pyridin-3-ylcarbonyl)furo[2,3-b]pyridin-3-yl]-N,N-dimethylurea,(23)N-[5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)-2-(pyridin-3-ylcarbonyl)furo[2,3-b]pyridin-3-yl]-2,2,2-trifluoroacetamide,(24)1-[3-amino-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)furo[2,3-b]pyridin-2-yl]propan-1-one,(25)N-[5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)-2-(2,2-dimethylpropanoyl)furo[2,3-b]pyridin-3-yl]-2,2,2-trifluoroacetamide,(26)1-[5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)-3-(methylamino)furo[2,3-b]pyridin-2-yl]-2,2-dimethylpropan-1-one,(27)1-[5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)-3-(dimethylamino)furo[2,3-bpyridin-2-yl]-2,2-dimethylpropan-1-one, (28)[5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)-3-(dimethylamino)furo[2,3-b]pyridin-2-yl](pyridin-3-yl)methanone,(29)3-amino-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)furo[2,3-b]pyridine-2-carbonitrile,and pharmaceutically acceptable salts thereof.
 12. The compoundaccording to claim 1 selected from: (1)N-[5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)-2-(2,2-dimethylpropanoyl)furo[2,3-b]pyridin-3-yl]butanamide,(2)N-[5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)-2-(2,2-dimethylpropanoyl)furo[2,3-b]pyridin-3-yl]pentanamide,(3) ethyl5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)-3-[(trifluoroacetyl)amino]furo[2,3-b]pyridine-2-carboxylate,(4)N-[5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)-2-(piperidin-1-ylcarbonyl)furo[2,3-b]pyridin-3-yl]-2,2,2-trifluoroacetamide,(5)5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)-2-(piperidin-1-ylcarbonyl)furo[2,3-b]pyridin-3-amine,(6)N-[5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)-2-(2,2-dimethylpropanoyl)furo[2,3-b]pyridin-3-yl]-2-methoxyacetamide,(7)N′-[5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)-2-(2,2-dimethylpropanoyl)furo[2,3-b]pyridin-3-yl]-N,N-dimethylurea,(8)N-[5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)-2-(2,2-dimethylpropanoyl)furo[2,3-b]pyridin-3-yl]morpholine-4-carboxamide,(9)N-[5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)-2-(2,2-dimethylpropanoyl)furo[2,3-b]pyridin-3-yl]-N′-ethylurea,(10)2-{[5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)-2-(2,2-dimethylpropanoyl)furo[2,3-b]pyridin-3-yl]amino}-2-oxoethylacetate, (11)N-[5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)-2-(2,2-dimethylpropanoyl)furo[2,3-b]pyridin-3-yl]-2-hydroxyacetamide,(12)1-[5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)-3-(ethylamino)furo[2,3-b]pyridin-2-yl]-2,2-dimethylpropan-1-one,(13)1-[3-amino-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)furo[2,3-b]pyridin-2-yl]-2-methylpropan-1-one,(14)[3-amino-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)furo[2,3-b]pyridin-2-yl](cyclopropyl)methanone,(15)[3-amino-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)furo[2,3-b]pyridin-2-yl](cyclobutyl)methanone,(16)N-[5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)-2-isobutyrylfuro[2,3-b]pyridin-3-yl]-2-hydroxyacetamide,(17)N-[5-(4-chlorophenyl)-2-(cyclobutylcarbonyl)-6-(2,4-dichlorophenyl)furo[2,3-b]pyridin-3-yl]-2-hydroxyacetamide,(18)4-chloro-N-[5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)-2-(2,2-dimethylpropanoyl)furo[2,3-b]pyridin-3-yl]butanamide,(19)1-[5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)-2-(2,2-dimethylpropanoyl)furo[2,3-b]pyridin-3-yl]pyrrolidin-2-one,(20)5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)-2-(3,4-difluorophenyl)furo[2,3-b]pyridin-3-ol,(21)1-[3-amino-6-(2-chlorophenyl)-5-(4-chlorophenyl)furo[2,3-b]pyridin-2-yl]-2,2-dimethylpropan-1-one,(22)N-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2,2-dimethylpropanoyl)furo[2,3-b]pyridin-3-yl]acetamide,(23)N-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2,2-dimethylpropanoyl)furo[2,3-b]pyridin-3-yl]-2-methoxyacetamide,(24)2-{[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2,2-dimethylpropanoyl)furo2,3-b]pyridin-3-yl]amino}-2-oxoethyl acetate, (25)N′-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2,2-dimethylpropanoyl)furo[2,3-b]pyridin-3-yl]-N,N-dimethylurea,(26)N-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2,2-dimethylpropanoyl)furo[2,3-b]pyridin-3-yl]methanesulfonamide,(27)N-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2,2-dimethylpropanoyl)furo[2,3-b]pyridin-3-yl]morpholine-4-carboxamide,(28)2-chloro-N-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2,2-dimethylpropanoyl)furo[2,3-b]pyridin-3-yl]acetamide,(29)(1S)-2-{[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2,2-dimethylpropanoyl)furo[2,3-b]pyridin-3-yl]amino}-1-methyl-2-oxoethylacetate, (30) ethyl[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2,2-dimethylpropanoyl)furo[2,3-b]pyridin-3-yl]carbamate,(31) ethyl[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2,2-dimethylpropanoyl)furo[2,3-b]pyridin-3-yl]amino}(oxo)acetate,(32)N-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2,2-dimethyl-propanoyl)furo[2,3-b]pyridin-3-yl]-1-(trifluoroacetyl)-(S)-prolinamide,(33)3-chloro-N-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2,2-dimethylpropanoyl)furo[2,3-b]pyridin-3-yl]propane-1-sulfonamide,(34)1-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-3-(dimethylamino)furo[2,3-b]pyridin-2-yl]-2,2-dimethylpropan-1-one,(35)1-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-3-(ethylamino)furo[2,3-b]pyridin-2-yl]-2,2-dimethylpropan-1-one,(36)N′-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2,2-dimethylpropanoyl)furo[2,3-b]pyridin-3-yl]-N,N-dimethylimidoformamide,(37)N-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2,2-dimethylpropanoyl)furo[2,3-b]pyridin-3-yl]acetamide,(38) tert-butyl[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2,2-dimethylpropanoyl)furo[2,3-b]pyridin-3-yl]carbamate,(39)1-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2,2-dimethylpropanoyl)furo[2,3-b]pyridin-3-yl]pyrrolidine-2,5-dione,(40)4-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2,2-dimethylpropanoyl)furo[2,3-b]pyridin-3-yl]morpholine-3,5-dione,(41)3-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2,2-dimethylpropanoyl)furo[2,3-b]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-2,4-dione,(42)(3S)-1-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2,2-dimethylpropanoyl)furo[2,3-b]pyridin-3-yl]-3-hydroxypyrrolidine-2,5-dione,(43)N-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2,2-dimethylpropanoyl)furo[2,3-b]pyridin-3-yl]-N-methylacetamide,(44)N-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2,2-dimethylpropanoyl)furo[2,3-b]pyridin-3-yl]-2-hydroxyacetamide,(45)N¹-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2,2-dimethylpropanoyl)furo[2,3-b]pyridin-3-yl]glycinamide,(46)N¹-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2,2-dimethylpropanoyl)furo[2,3-b]pyridin-3-yl]-N²-methylglycinamide,(47)N¹-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2,2-dimethylpropanoyl)furo[2,3-b]pyridin-3-yl]-N²,N²-dimethylglycinamide,(48)(2S)-N-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2,2-dimethylpropanoyl)furo[2,3-b]pyridin-3-yl]-2-hydroxypropanamide, (49) ethylallyl[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2,2-dimethylpropanoyl)furo[2,3-b]pyridin-3-yl]carbamate,(50) ethyl[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2,2-dimethylpropanoyl)furo[2,3-b]pyridin-3-yl][2-(dimethylamino)ethyl]carbamate, (51)1-[3-(allylamino)-6-(2-chlorophenyl)-5-(4-chlorophenyl)furo[2,3-b]pyridin-2-yl]-2,2-dimethylpropan-1-one,(52)1-(6-(2-chlorophenyl)-5-(4-chlorophenyl)-3-{[2-(dimethylamino)ethyl]amino}furo[2,3-b]pyridin-2-yl)-2,2-dimethylpropan-1-one,(53)N-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2,2-dimethylpropanoyl)furo[2,3-b]pyridin-3-yl]-L-prolinamide,(54)1-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-3-(1,1-dioxidoisothiazolidin-2-yl)furo[2,3-b]pyridin-2-yl]-2,2-dimethylpropan-1-one,(55)1-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2,2-dimethylpropanoyl)furo[2,3-b]pyridin-3-yl]-3-methylimidazolidin-2-one,(56)1-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2-hydroxy-2-methylpropanoyl)furo[2,3-b]pyridin-3-yl]-3-methylimidazolidine-2,4-dione, (57)1-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2,2-dimethylpropanoyl)furo[2,3-b]pyridin-3-yl]-4-methylpiperazine-2,3-dione,(58)1-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2,2-dimethylpropanoyl)furo[2,3-b]pyridin-3-yl]-4-methylpiperazine-2,5-dione,(59)1-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-3-hydroxyfuro[2,3-b]pyridin-2-yl]-2,2-dimethylpropan-1-one,(60)1-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-3-methylfuro[2,3-b]pyridin-2-yl]-2,2-dimethylpropan-1-one,(61) 6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2,2-dimethylpropanoyl)furo[2,3-b]pyridine-3-carbaldehyde, (62) methyl6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2,2-dimethylpropanoyl)furo[2,3-b]pyridine-3-carboxylate,(63)6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2,2-dimethylpropanoyl)-N,N-diethylfuro[2,3-b]pyridine-3-carboxamide,(64)1-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-3-(4H-1,2,4-triazol-4-yl)furo[2,3-b]pyridin-2-yl]-2,2-dimethylpropan-1-one,(65)1-[6-(2-chlorophenyl)-5-(4-chlorophenyl)furo[2,3-b]pyridin-2-yl]-2,2-dimethylpropan-1-one,(66)1-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-3-(pyridin-2-ylamino)furo[2,3-b]pyridin-2-yl]-2,2-dimethylpropan-1-one,(67)1-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-3-(pyridin-2-ylamino)-furo[2,3-b]pyridin-2-yl]-2,2-dimethylpropan-1-one,(68)1-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-3-(pyrimidin-5-ylamino)-furo[2,3-b]pyridin-2-yl]-2,2-dimethylpropan-1-one,(69)1-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-3-(pyridin-3-ylamino)-furo[2,3-b]pyridin-2-yl]-2,2-dimethylpropan-1-one,(70)1-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-3-(pyridin-4-ylamino)-furo[2,3-b]pyridin-2-yl]-2,2-dimethylpropan-1-one,(71)1-[3-amino-6-(2-chlorophenyl)-5-(4-chlorophenyl)furo[2,3-b]pyridin-2-yl]-2-hydroxy-2-methylpropan-1-one,(72)N-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2-hydroxy-2-methylpropanoyl)furo[2,3-b]pyridin-3-yl]cyclopropanecarboxamide,(73)N-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2-hydroxy-2-methylpropanoyl)furo[2,3-b]pyridin-3-yl]-2-methylpropanamide,(74)N-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2-hydroxy-2-methylpropanoyl)furo[2,3-b]pyridin-3-yl]-3-methylbutanamide,(75)N-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2-hydroxy-2-methylpropanoyl)furo[2,3-b]pyridin-3-yl]butanamide,(76)N-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2-hydroxy-2-methylpropanoyl)furo[2,3-b]pyridin-3-yl]propanamide,(77)N-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2-hydroxy-2-methylpropanoyl)furo[2,3-b]pyridin-3-yl]-2-methoxyacetamide,(78)N-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2-hydroxy-2-methylpropanoyl)furo[2,3-b]pyridin-3-yl]-2-hydroxy-2-methylpropanamide,(79)4-chloro-N-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2-hydroxy-2-methylpropanoyl)furo[2,3-b]pyridin-3-yl]butanamide,(80)1-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2-hydroxy-2-methylpropanoyl)furo[2,3-b]pyridin-3-yl]pyrrolidin-2-one,(81)N-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2-hydroxy-2-methylpropanoyl)furo[2,3-b]pyridin-3-yl]sulfamide,(82)2-chloro-N-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2-hydroxy-2-methylpropanoyl)furo[2,3-b]pyridin-3-yl]acetamide,(83)N¹-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2-hydroxy-2-methylpropanoyl)furo[2,3-b]pyridin-3-yl]-N²-methylglycinamide,(84)N²-acetyl-N¹-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2-hydroxy-2-methylpropanoyl)furo[2,3-b]pyridin-3-yl]-N²-methylglycinamide,(85)2-azetidin-1-yl-N-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2-hydroxy-2-methylpropanoyl)furo[2,3-b]pyridin-3-yl]acetamide,(86)N-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2-hydroxy-2-methylpropanoyl)furo[2,3-b]pyridin-3-yl]-2-(1H-imidazol-1-yl)acetamide,(87)1-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2-hydroxy-2-methylpropanoyl)furo[2,3-b]pyridin-3-yl]pyrrolidine-2,5-dione,(88) methyl3-{[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2-hydroxy-2-methylpropanoyl)furo[2,3-b]pyridin-3-yl]amino}-3-oxopropanoate,(89)N²-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2-hydroxy-2-methylpropanoyl)furo[2,3-b]pyridin-3-yl]-N¹,N¹-dimethylglycinamide,(90) ethyl[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2-hydroxy-2-methylpropanoyl)furo[2,3-b]pyridin-3-yl]carbamate,(91)N′-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2-hydroxy-2-methylpropanoyl)furo[2,3-b]pyridin-3-yl]-N,N-dimethylethanediamide,(92)N-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2-hydroxy-2-methylpropanoyl)furo[2,3-b]pyridin-3-yl]-N′-methylethanediamide,(93)N-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2-hydroxy-2-methylpropanoyl)furo[2,3-b]pyridin-3-yl]-N¹-(2-hydroxyethyl)ethanediamide,(94)N-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2-hydroxy-2-methylpropanoyl)furo[2,3-b]pyridin-3-yl]-N′-ethylethanediamide,(95)N-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2-hydroxy-2-methylpropanoyl)furo[2,3-b]pyridin-3-yl]-2-oxo-2-pyrrolidin-1-ylacetamide,(96)N-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2-hydroxy-2-methylpropanoyl)furo[2,3-b]pyridin-3-yl]-N′-ethylurea,(97)N-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2-hydroxy-2-methylpropanoyl)furo[2,3-b]pyridin-3-yl]morpholine-4-carboxamide,(98)N-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2-hydroxy-2-methylpropanoyl)furo[2,3-b]pyridin-3-yl]pyrrolidine-1-carboxamide,(99)1-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-3-(methylamino)furo[2,3-b]pyridin-2-yl]-2-hydroxy-2-methylpropan-1-one,(100)1-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2-hydroxy-2-methylpropanoyl)furo[2,3-b]pyridin-3-yl]imidazolidine-2,4-dione,(101)1-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2-hydroxy-2-methylpropanoyl)furo[2,3-b]pyridin-3-yl]-3-methylimidazolidin-2-one,(102)1-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2-hydroxy-2-methylpropanoyl)furo[2,3-b]pyridin-3-yl]-3-3-methylimidazolidine-2,4-dione,(103)3-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2-hydroxy-2-methylpropanoyl)furo[2,3-b]pyridin-3-yl]-1,3-oxazolidin-2-one,(104)N-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2-hydroxy-2-methylpropanoyl)furo[2,3-b]pyridin-3-yl]-N′,2,2-trimethylmalonamide,(105)N-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2-hydroxy-2-methylpropanoyl)furo[2,3-b]pyridin-3-yl]-(S)-prolinamide,(106)1-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-3-(1,1-dioxidoisothiazolidin-2-yl)furo[2,3-b]pyridin-2-yl]-2-hydroxy-2-methylpropan-1-one,(107)N-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2-hydroxy-2-methylpropanoyl)furo[2,3-b]pyridin-3-yl]-2,2-dimethylmalonamide,(108)1-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-3-methylfuro[2,3-b]pyridin-2-yl]-2-hydroxy-2-methylpropan-1-one,(109)1-[3-amino-6-(2-chlorophenyl)-5-(4-chlorophenyl)furo[2,3-b]pyridin-2-yl]-2-methylpropan-1-one,(110)2-{[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-isobutyrylfuro[2,3-b]pyridin-3-yl]amino}-2-oxoethylacetate, (111)N-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-isobutyrylfuro[2,3-b]pyridin-3-yl]-2-hydroxyacetamide,(112)N-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-isobutyrylfuro[2,3-b]pyridin-3-yl]-2-hydroxy-N-methylacetamide,(113)N-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-isobutyrylfuro[2,3-b]pyridin-3-yl]acetamide,(114)4-chloro-N-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-isobutyrylfuro[2,3-b]pyridin-3-yl]butanamide,(115)1-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-isobutyrylfuro[2,3-b]pyridin-3-yl]pyrrolidin-2-one,(116)N-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-isobutyrylfuro[2,3-b]pyridin-3-yl]-N-methylacetamide,(117)1-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-isobutyrylfuro[2,3-b]pyridin-3-yl]pyrrolidine-2,5-dione,(118)4-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-isobutyrylfuro[2,3-b]pyridin-3-yl]morpholine-3,5-dione,(119)N-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-isobutyrylfuro[2,3-b]pyridin-3-yl]methanesulfonamide,(120)1-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-isobutyrylfuro[2,3-b]pyridin-3-yl]imidazolidine-2,4-dione,(121)N-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-isobutyrylfuro[2,3-b]pyridin-3-yl]urea,(122)1-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-isobutyrylfuro[2,3-b]pyridin-3-yl]piperidine-2,6-dione,(123)3-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-isobutyrylfuro[2,3-b]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-2,4-dione,(124)1-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-3-(1,1-dioxidoisothiazolidin-2-yl)furo[2,3-b]pyridin-2-yl]-2-methylpropan-1-one,(125)N-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-isobutyrylfuro[2,3-b]pyridin-3-yl]-N-methylmethanesulfonamide,(126)[3-amino-6-(2-chlorophenyl)-5-(4-chlorophenyl)furo[2,3-b]pyridin-2-yl](pyridin-3-yl)methanone,(127)N-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(pyridin-3-ylcarbonyl)furo[2,3-b]pyridin-3-yl]-2-hydroxyacetamide,(128)[3-amino-6-(2-chlorophenyl)-5—(4-chlorophenyl)furo[2,3-b]pyridin-2-yl](2-furyl)-methanone,(129)N-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2-furoyl)furo[2,3-b]pyridin-3-yl]acetamide,(130)N-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(2-furoyl)furo[2,3-b]pyridin-3-yl]acetamide,(131) 2-(tert-butylsulfonyl)-6-(2-chlorophenyl)-5-(4-chlorophenyl)furo[2,3-b]pyridin-3-amine, (132)N-[2-(tert-butylsulfonyl)-6-(2-chlorophenyl)-5-(4-chlorophenyl)-furo[2,3-b]pyridin-3-yl]methanesulfonamide,(133)N-[2-(tert-butylsulfonyl)-6-(2-chlorophenyl)-5-(4-chlorophenyl)-furo[2,3-b]pyridin-3-yl]acetimide,(134)N-[2-(tert-butylsulfonyl)-6-(2-chlorophenyl)-5-(4-chlorophenyl)-furo[2,3-b]pyridin-3-yl]acetamide,(135)2-{[2-(tert-butylsulfonyl)-6-(2-chlorophenyl)-5-(4-chlorophenyl)-furo[2,3-b]pyridin-3-yl]amino}-2-oxoethylacetate, (136)N-[2-(tert-butylsulfonyl)-6-(2-chlorophenyl)-5-(4-chlorophenyl)-furo[2,3-b]pyridin-3-yl]-2-hydroxyacetamide,(137)1-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(methylsulfonyl)-furo[2,3-b]pyridin-3-yl]pyrrolidine-2,5-dione,(138)N-[2-(tert-butylsulfonyl)-6-(2-chlorophenyl)-5-(4-chlorophenyl)-furo[2,3-b]pyridin-3-yl]-N-methylmethanesulfonamide,(139)N-[2-(tert-butylsulfonyl)-6-(2-chlorophenyl)-5-(4-chlorophenyl)-furo[2,3-b]pyridin-3-yl]-N-methylacetamide,(140)1-[2-(tert-butylsulfonyl)-6-(2-chlorophenyl)-5-(4-chlorophenyl)-furo[2,3-b]pyridin-3-yl]imidazolidine-2,4-dione,(141)6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(phenylsulfonyl)furo[2,3-b]pyridin-3-amine,(142)2-{[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(phenylsulfonyl)furo[2,3-b]pyridin-3-yl]amino}-2-oxoethylacetate, (143)N-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(phenylsulfonyl)furo[2,3-b]pyridin-3-yl]-2-hydroxyacetamide,(144)2-chloro-N-({[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(phenylsulfonyl)furo[2,3-b]pyridin-3-yl]amino}carbonyl)acetamide,(145)1-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(phenylsulfonyl)furo[2,3-b]pyridin-3-yl]imidazolidine-2,4-dione,(146)6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(methylsulfonyl)furo[2,3-b]pyridin-3-amine,(147)N-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(methylsulfonyl)-furo[2,3-b]pyridine-3-yl]acetamide,(148)N-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(methylsulfonyl)-furo[2,3-b]pyridin-3-yl]butanamide,(149) ethyl3-amino-6-(2-chlorophenyl)-5-(4-chlorophenyl)furo[2,3-b]pyridine-2-carboxylate,(150) ethyl6-(2-chlorophenyl)-5-(4-chlorophenyl)-3-[(trifluoroacetyl)amino]furo[2,3-b]pyridine-2-carboxylate,(151)6-(2-chlorophenyl)-5-(4-chlorophenyl)-N,N-diethyl-3-[(trifluoroacetyl)amino]furo[2,3-b]pyridine-2-carboxamide,(152)3-amino-6-(2-chlorophenyl)-5-(4-chlorophenyl)-N,N-diethylfuro[2,3-b]pyridine-2-carboxamide,(153)3-(acetylamino)-6-(2-chlorophenyl)-5-(4-chlorophenyl)-N,N-diethylfuro[2,3-b]pyridine-2-carboxamide,(154)3-(acetylamino)-6-(2-chlorophenyl)-5-(4-chlorophenyl)-N-ethyl-N-methylfuro[2,3-b]pyridine-2-carboxamide,(155)6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(piperidin-1-ylcarbonyl)furo[2,3-b]pyridin-3-amine,(156)N-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(piperidin-1-ylcarbonyl)furo[2,3-b]pyridin-3-yl]acetamide,(157)6-(2-chlorophenyl)-5-(4-chlorophenyl)-N,N-diethyl-3-(glycoloylamino)furo[2,3-b]pyridine-2-carboxamide,(158)6-(2-chlorophenyl)-5-(4-chlorophenyl)-3-(glycoloylamino)-N,N-dimethylfuro[2,3-b]pyridine-2-carboxamide,(159)6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(pyrrolidin-1-ylcarbonyl)furo[2,3-b]pyridin-3-amine,(160)1-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(pyrrolidin-1-ylcarbonyl)furo[2,3-b]pyridin-3-yl]pyrrolidine-2,5-dione,(161)1-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-(pyrrolidin-1-ylcarbonyl)furo[2,3-b]pyridin-3-yl]-3-methylimidazolidine-2,4-dione,(162)6-(2-chlorophenyl)-5-(4-chlorophenyl)-3-(2,4-dioxoimidazolidin-1-yl)-N,N-diethylfuro[2,3-b]pyridine-2-carboxamide,(163)6-(2-chlorophenyl)-5-(4-chlorophenyl)-N,N-diethyl-3-[(methylsulfonyl)amino]furo[2,3-b]pyridine-2-carboxamide,(164)6-(2-chlorophenyl)-5-(4-chlorophenyl)-N,N-diethyl-3-[(propylsulfonyl)amino]furo[2,3-b]pyridine-2-carboxamide,(165)6-(2-chlorophenyl)-5-(4-chlorophenyl)-3-(2,5-dioxopyrrolidin-1-yl)-N,N-diethylfuro[2,3-b]pyridine-2-carboxamide,(166)1-[6-(2-chlorophenyl)-5-(4-chlorophenyl)-3-(1-methyl-1H-imidazol-2-yl)furo[2,3-b]pyridin-2-yl]-2,2-dimethylpropan-1-one,(167)4-[3-amino-5-(4-chlorophenyl)-2-(2-hydroxy-2-methylpropanoyl)furo[2,3-b]pyridin-6-yl]-3-chlorobenzonitrile,(168)N-[6-(2-chloro-4-cyanophenyl)-5-(4-chlorophenyl)-2-(2-hydroxy-2-methylpropanoyl)furo[2,3-b]pyridin-3-yl]acetamide,(169)3-[3-amino-6-(2,4-dichlorophenyl)-2-(2,2-dimethylpropanoyl)furo[2,3-b]pyridin-5-yl]benzonitrile,(170)4-[3-amino-6-(2-chlorophenyl)-2-(2-hydroxy-2-methylpropanoyl)furo[2,3-b]pyridin-5-yl]benzonitrile,(171)N-[6-(2-chlorophenyl)-5-(4-cyanophenyl)-2-(2-hydroxy-2-methylpropanoyl)furo[2,3-b]pyridin-3-yl]acetamide,(172)1-[3-amino-6-(1,3-benzodioxol-5-yl)-5-(4-chlorophenyl)furo[2,3-b]pyridin-2-yl]-2,2-dimethylpropan-1-one,(173)1-[3-amino-6-(2-chloro-4-fluorophenyl)-5-(4-chlorophenyl)furo[2,3-b]pyridin-2-yl]-2,2-dimethylpropan-1-one,(174)N-[6-(2-chloro-4-fluorophenyl)-5-(4-chlorophenyl)-2-(2,2-dimethylpropanoyl)furo[2,3-b]pyridin-3-yl]-2-methoxyacetamide,(175)N-[6-(2-chloro-4-fluorophenyl)-5-(4-chlorophenyl)-2-(2-hydroxy-2-methylpropanoyl)furo[2,3-b]pyridin-3-yl]-2-hydroxyacetamide,(176)N-[5-(4-chlorophenyl)-6-(2-cyanophenyl)-2-(2-hydroxy-2-methylpropanoyl)furo[2,3-b]pyridin-3-yl]acetamide,(177)N-[5-(4-chlorophenyl)-6-(2-cyanophenyl)-2-(2,2-dimethylpropanoyl)furo[2,3-b]pyridin-3-yl]acetamide,(178)N-[5-(4-chlorophenyl)-6-(2-cyanophenyl)-2-(2,2-dimethylpropanoyl)furo[2,3-b]pyridin-3-yl]-2-hydroxyacetamide,(179)N-[6-(4-chloro-2-cyanophenyl)-5-(4-chlorophenyl)-2-(2-hydroxy-2-methylpropanoyl)furo[2,3-b]pyridin-3-yl]acetamide,(180)N-[6-(2-chlorophenyl)-2-(2-hydroxy-2-methylpropanoyl)-5-(4-methoxyphenyl)furo[2,3-b]pyridin-3-yl]acetamide,(181)N-[6-(2-chlorophenyl)-2-(2,2-dimethylpropanoyl)-5-(4-methoxyphenyl)furo[2,3-b]pyridin-3-yl]acetamide,and pharmaceutically acceptable salts thereof.
 13. A method of treatinga disease mediated by the Cannabinoid-1 receptor comprisingadministration to a patient in need of such treatment of atherapeutically effective amount of a compound according to claim
 1. 14.The method according to claim 13 wherein the disease mediated by theCannabinoid-1 receptor is selected from: psychosis, memory deficit,cognitive disorders, migraine, neuropathy, neuro-inflammatory disorders,cerebral vascular accidents, head trauma, anxiety disorders, stress,epilepsy, Parkinson's disease, schizophrenia, substance abuse disorders,constipation, chronic intestinal pseudo-obstruction, cirrhosis of theliver, asthma, obesity, and other eating disorders associated withexcessive food intake.
 15. The method according to claim 14 wherein thedisease mediated by the Cannabinoid-1 receptor is an eating disorderassociated with excessive food intake.
 16. The method according to claim15 wherein the eating disorder associated with excessive food intake isselected from obesity, bulimia nervosa, and compulsive eating disorders.17. The method according to claim 16 wherein the eating disorderassociated with excessive food intake is obesity.
 18. A method ofpreventing obesity in a person at risk for obesity comprisingadministration to said person of about 0.001 mg to about 100 mg per kgof a compound according to claim
 1. 19. A composition comprising acompound according to claim 1 and a pharmaceutically acceptable carrier.20 to
 25. (canceled)